JPH05501567A - Metal-peptide compositions and methods for stimulating hair growth - Google Patents
Metal-peptide compositions and methods for stimulating hair growthInfo
- Publication number
- JPH05501567A JPH05501567A JP3500560A JP50056091A JPH05501567A JP H05501567 A JPH05501567 A JP H05501567A JP 3500560 A JP3500560 A JP 3500560A JP 50056091 A JP50056091 A JP 50056091A JP H05501567 A JPH05501567 A JP H05501567A
- Authority
- JP
- Japan
- Prior art keywords
- carbon atoms
- glycyl
- histidyl
- copper
- valyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 230000003779 hair growth Effects 0.000 title claims description 70
- 239000000203 mixture Substances 0.000 title claims description 33
- 230000004936 stimulating effect Effects 0.000 title claims description 12
- 238000000034 method Methods 0.000 title description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 79
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 claims description 63
- 239000007924 injection Substances 0.000 claims description 37
- 238000002347 injection Methods 0.000 claims description 37
- 239000010949 copper Substances 0.000 claims description 35
- 229910021645 metal ion Inorganic materials 0.000 claims description 32
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 claims description 30
- XLJKHNWPARRRJB-UHFFFAOYSA-N cobalt(2+) Chemical compound [Co+2] XLJKHNWPARRRJB-UHFFFAOYSA-N 0.000 claims description 29
- WAEMQWOKJMHJLA-UHFFFAOYSA-N Manganese(2+) Chemical compound [Mn+2] WAEMQWOKJMHJLA-UHFFFAOYSA-N 0.000 claims description 28
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 27
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 claims description 24
- 229910052802 copper Inorganic materials 0.000 claims description 21
- 229960004295 valine Drugs 0.000 claims description 21
- 229910052793 cadmium Inorganic materials 0.000 claims description 20
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical group [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 claims description 20
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical group [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 19
- 239000004472 Lysine Substances 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 125000004104 aryloxy group Chemical group 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- IUTCEZPPWBHGIX-UHFFFAOYSA-N tin(2+) Chemical compound [Sn+2] IUTCEZPPWBHGIX-UHFFFAOYSA-N 0.000 claims description 16
- 229960004799 tryptophan Drugs 0.000 claims description 15
- 125000003282 alkyl amino group Chemical group 0.000 claims description 14
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims description 13
- IFGCUJZIWBUILZ-UHFFFAOYSA-N sodium 2-[[2-[[hydroxy-(3,4,5-trihydroxy-6-methyloxan-2-yl)oxyphosphoryl]amino]-4-methylpentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid Chemical compound [Na+].C=1NC2=CC=CC=C2C=1CC(C(O)=O)NC(=O)C(CC(C)C)NP(O)(=O)OC1OC(C)C(O)C(O)C1O IFGCUJZIWBUILZ-UHFFFAOYSA-N 0.000 claims description 13
- 239000000126 substance Substances 0.000 claims description 13
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 229910052751 metal Inorganic materials 0.000 claims description 12
- 239000002184 metal Substances 0.000 claims description 12
- MVORZMQFXBLMHM-QWRGUYRKSA-N Gly-His-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](NC(=O)CN)CC1=CN=CN1 MVORZMQFXBLMHM-QWRGUYRKSA-N 0.000 claims description 10
- 241001465754 Metazoa Species 0.000 claims description 10
- MJOUSKQHAIARKI-JYJNAYRXSA-N Val-Phe-Val Chemical compound CC(C)[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](C(C)C)C(O)=O)CC1=CC=CC=C1 MJOUSKQHAIARKI-JYJNAYRXSA-N 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 125000004429 atom Chemical group 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- VLMNBMFYRMGEMB-QWRGUYRKSA-N Lys-His-Gly Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(=O)NCC(O)=O)CC1=CNC=N1 VLMNBMFYRMGEMB-QWRGUYRKSA-N 0.000 claims description 6
- 230000000699 topical effect Effects 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- WLZRMCYVCSSEQC-UHFFFAOYSA-N cadmium(2+) Chemical group [Cd+2] WLZRMCYVCSSEQC-UHFFFAOYSA-N 0.000 claims 7
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical group OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 claims 2
- 206010028980 Neoplasm Diseases 0.000 claims 2
- WZGNVVUXVXNNOX-UHFFFAOYSA-N [Fe+] Chemical compound [Fe+] WZGNVVUXVXNNOX-UHFFFAOYSA-N 0.000 claims 2
- 201000011510 cancer Diseases 0.000 claims 2
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims 1
- LIASWTUFJMBWEN-UHFFFAOYSA-N [Mn+] Chemical compound [Mn+] LIASWTUFJMBWEN-UHFFFAOYSA-N 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- -1 octyl ester Chemical class 0.000 description 37
- 239000000243 solution Substances 0.000 description 37
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- 241000699670 Mus sp. Species 0.000 description 32
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 210000004209 hair Anatomy 0.000 description 20
- 230000000638 stimulation Effects 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 18
- 238000003786 synthesis reaction Methods 0.000 description 18
- 239000000047 product Substances 0.000 description 17
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
- 239000008194 pharmaceutical composition Substances 0.000 description 15
- 239000010410 layer Substances 0.000 description 14
- 150000002148 esters Chemical class 0.000 description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- 241000699666 Mus <mouse, genus> Species 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 12
- 210000003491 skin Anatomy 0.000 description 12
- 229960002885 histidine Drugs 0.000 description 11
- 210000004003 subcutaneous fat Anatomy 0.000 description 11
- 201000004384 Alopecia Diseases 0.000 description 10
- 108010016626 Dipeptides Proteins 0.000 description 10
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 108010038983 glycyl-histidyl-lysine Proteins 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- 238000011282 treatment Methods 0.000 description 8
- 229940024606 amino acid Drugs 0.000 description 7
- 235000001014 amino acid Nutrition 0.000 description 7
- 150000001413 amino acids Chemical class 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
- 239000012362 glacial acetic acid Substances 0.000 description 7
- 230000004044 response Effects 0.000 description 7
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 6
- 239000006071 cream Substances 0.000 description 6
- 238000004811 liquid chromatography Methods 0.000 description 6
- 230000007935 neutral effect Effects 0.000 description 6
- 230000002441 reversible effect Effects 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000004471 Glycine Substances 0.000 description 5
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical class CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 230000003676 hair loss Effects 0.000 description 4
- 238000001000 micrograph Methods 0.000 description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 4
- 239000011736 potassium bicarbonate Substances 0.000 description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000004474 valine Substances 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 210000001789 adipocyte Anatomy 0.000 description 3
- 231100000360 alopecia Toxicity 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000001574 biopsy Methods 0.000 description 3
- 230000003778 catagen phase Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 239000007822 coupling agent Substances 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 239000003623 enhancer Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 210000003780 hair follicle Anatomy 0.000 description 3
- 208000024963 hair loss Diseases 0.000 description 3
- 210000004919 hair shaft Anatomy 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000002563 ionic surfactant Substances 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 230000035515 penetration Effects 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 238000010254 subcutaneous injection Methods 0.000 description 3
- 239000007929 subcutaneous injection Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- SZXBQTSZISFIAO-ZETCQYMHSA-N (2s)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]butanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)OC(C)(C)C SZXBQTSZISFIAO-ZETCQYMHSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- LYCVKHSJGDMDLM-LURJTMIESA-N His-Gly Chemical compound OC(=O)CNC(=O)[C@@H](N)CC1=CN=CN1 LYCVKHSJGDMDLM-LURJTMIESA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical group CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- CJUMAFVKTCBCJK-UHFFFAOYSA-N N-benzyloxycarbonylglycine Chemical compound OC(=O)CNC(=O)OCC1=CC=CC=C1 CJUMAFVKTCBCJK-UHFFFAOYSA-N 0.000 description 2
- IEHDJWSAXBGJIP-RYUDHWBXSA-N Phe-Val Chemical compound CC(C)[C@@H](C([O-])=O)NC(=O)[C@@H]([NH3+])CC1=CC=CC=C1 IEHDJWSAXBGJIP-RYUDHWBXSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- YIRBOOICRQFSOK-NSHDSACASA-N benzyl (2s)-2-amino-3-methylbutanoate Chemical compound CC(C)[C@H](N)C(=O)OCC1=CC=CC=C1 YIRBOOICRQFSOK-NSHDSACASA-N 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 229960000541 cetyl alcohol Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
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- 238000000605 extraction Methods 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
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- 108010036413 histidylglycine Proteins 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
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- 239000007788 liquid Substances 0.000 description 2
- 125000001288 lysyl group Chemical group 0.000 description 2
- 229910001510 metal chloride Inorganic materials 0.000 description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 2
- IOQPZZOEVPZRBK-UHFFFAOYSA-N octan-1-amine Chemical compound CCCCCCCCN IOQPZZOEVPZRBK-UHFFFAOYSA-N 0.000 description 2
- 108010084572 phenylalanyl-valine Proteins 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
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- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 2
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- 239000007787 solid Substances 0.000 description 2
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- 239000002904 solvent Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
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- 230000009897 systematic effect Effects 0.000 description 2
- XKXIQBVKMABYQJ-UHFFFAOYSA-N tert-butyl hydrogen carbonate Chemical compound CC(C)(C)OC(O)=O XKXIQBVKMABYQJ-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- ZYJPUMXJBDHSIF-NSHDSACASA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZYJPUMXJBDHSIF-NSHDSACASA-N 0.000 description 1
- VUZJKGCTMGVVKX-LURJTMIESA-N (2s)-3-(1h-imidazol-5-yl)-2-(methoxycarbonylamino)propanoic acid Chemical compound COC(=O)N[C@H](C(O)=O)CC1=CNC=N1 VUZJKGCTMGVVKX-LURJTMIESA-N 0.000 description 1
- FFJCNSLCJOQHKM-CLFAGFIQSA-N (z)-1-[(z)-octadec-9-enoxy]octadec-9-ene Chemical compound CCCCCCCC\C=C/CCCCCCCCOCCCCCCCC\C=C/CCCCCCCC FFJCNSLCJOQHKM-CLFAGFIQSA-N 0.000 description 1
- NKTAFVCXHYXTQK-UHFFFAOYSA-N 1,1,1-trichloro-3-methylbutane Chemical compound CC(C)CC(Cl)(Cl)Cl NKTAFVCXHYXTQK-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
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- ZQXCQTAELHSNAT-UHFFFAOYSA-N 1-chloro-3-nitro-5-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC(Cl)=CC(C(F)(F)F)=C1 ZQXCQTAELHSNAT-UHFFFAOYSA-N 0.000 description 1
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- 229910017052 cobalt Inorganic materials 0.000 description 1
- GSOLWAFGMNOBSY-UHFFFAOYSA-N cobalt Chemical compound [Co][Co][Co][Co][Co][Co][Co][Co] GSOLWAFGMNOBSY-UHFFFAOYSA-N 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- NZWIFMYRRCMYMN-ACMTZBLWSA-M copper;(2s)-6-amino-2-[[(2s)-2-[(2-aminoacetyl)amino]-3-(1h-imidazol-5-yl)propanoyl]amino]hexanoate Chemical class [Cu+2].NCCCC[C@@H](C([O-])=O)NC(=O)[C@@H](NC(=O)CN)CC1=CN=CN1 NZWIFMYRRCMYMN-ACMTZBLWSA-M 0.000 description 1
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- 239000003480 eluent Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 1
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- QTBFPMKWQKYFLR-UHFFFAOYSA-N isobutyl chloride Chemical compound CC(C)CCl QTBFPMKWQKYFLR-UHFFFAOYSA-N 0.000 description 1
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- 239000006210 lotion Substances 0.000 description 1
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- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 229960003632 minoxidil Drugs 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- GLDOVTGHNKAZLK-UHFFFAOYSA-N n-octadecyl alcohol Natural products CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical group C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- CDKDZKXSXLNROY-UHFFFAOYSA-N octylbenzene Chemical compound CCCCCCCCC1=CC=CC=C1 CDKDZKXSXLNROY-UHFFFAOYSA-N 0.000 description 1
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- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
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- 235000019271 petrolatum Nutrition 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
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- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 1
- 230000036332 sexual response Effects 0.000 description 1
- 238000007390 skin biopsy Methods 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
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- 229910052717 sulfur Inorganic materials 0.000 description 1
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- 230000003797 telogen phase Effects 0.000 description 1
- FBWNMEQMRUMQSO-UHFFFAOYSA-N tergitol NP-9 Chemical group CCCCCCCCCC1=CC=C(OCCOCCOCCOCCOCCOCCOCCOCCOCCO)C=C1 FBWNMEQMRUMQSO-UHFFFAOYSA-N 0.000 description 1
- UJJDEOLXODWCGK-UHFFFAOYSA-N tert-butyl carbonochloridate Chemical group CC(C)(C)OC(Cl)=O UJJDEOLXODWCGK-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q7/00—Preparations for affecting hair growth
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0815—Tripeptides with the first amino acid being basic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/58—Metal complex; Coordination compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
(57)【要約】本公報は電子出願前の出願データであるため要約のデータは記録されません。 (57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.
Description
【発明の詳細な説明】 本発明は、一般に毛髪成長の刺激に関するものであり、更に詳しくは、活性治療 物質として、また毛髪成長を刺激するための薬剤の製造に使用するための金属− ペプチド組成物に関する。本発明の金属−ペプチド組成物はグリシルルーヒスチ ジル−し−リシン、Ｌ−リシルルーヒスチジル−グリシン及びこれらの誘導体の 金属キレートを含む。[Detailed description of the invention] FIELD OF THE INVENTION This invention relates generally to the stimulation of hair growth, and more particularly to the stimulation of hair growth. Metals as substances and for use in the manufacture of drugs for stimulating hair growth - The present invention relates to peptide compositions. The metal-peptide composition of the present invention Dyl-cylysine, L-lysyl-histidyl-glycine and their derivatives Contains metal chelates.
発明の背景 脱毛は人間の普通の病気であり、最も典型的なものは男性が年齢とともに頭髪を 失う“脱毛症” （男性パターンはげ）である。毛髪は通常二つの型、“硬毛” 及び“軟毛”に分けられる。硬毛は、皮膚内の深部に発達される小胞から生じる 粗い着色毛髪である。軟毛は、典型的には、それより小さくて皮膚中の表面近く に配置される毛嚢から成長する細い無着色の毛髪である。脱毛症が進行するにつ れて、硬毛から軟毛型の毛髪への一般の変化がある。Background of the invention Hair loss is a common human disease, most commonly caused by men losing their hair as they age. This is "alopecia" (male pattern baldness). Hair usually comes in two types: terminal hair and “vellus hair”. Terminal hairs arise from vesicles that develop deep within the skin Coarse colored hair. Vellus hairs are typically smaller and located near the surface of the skin They are thin, unpigmented hairs that grow from hair follicles located in the hair. As alopecia progresses There is a general change from terminal hair to vellus type hair.
脱毛症に関連するその他の変化は毛髪の成長サイクルの変化である。毛髪（ま典 型的には三つのサイクル、即ち、発育期（活性な毛髪成長）、退行期（ｃａｔａ ｇｅｎ）（転移段階）、及び休止期（毛幹が新たな成長の前に脱落される静止段 階口こより発達する。はげが進行するにつれて、夫々の段階で毛嚢の比率に変化 があり、その殆どが発育期から休止期まで変化する。また、毛嚢のサイズが減少 することが知られているが、合計数は比較的一定のままである。Other changes associated with alopecia are changes in the hair growth cycle. hair Typically, there are three cycles: the anagen phase (active hair growth), the catagen phase (catagen phase) and the catagen phase (active hair growth). gen) (transitional stage), and telogen (resting stage where the hair shaft is shed before new growth). It develops from the floor entrance. As baldness progresses, the ratio of hair follicles changes at each stage. Most of them change from the developmental stage to the resting stage. Also, the size of hair follicles decreases is known to occur, but the total number remains relatively constant.
脱毛の普通の治療は毛髪の移植であった。簡単に言えば、毛髪を含む皮膚のプラ グが、毛髪が成長しつつある頭の領域からはげの領域に移植される。この操作は 、時間を浪費し、比較的痛みがあることに加えて、コストがかかるものである。A common treatment for hair loss has been hair transplantation. Simply put, skin plastics including hair The hair is transplanted from the area of the head where hair is growing into the bald area. This operation In addition to being time consuming and relatively painful, it is also costly.
その他の治療は紫外線照射及び切開治療を含んでいた。しかしながら、これらｔ ′ｉ有効であるとして一般にに受入れられていなかった。Other treatments included ultraviolet radiation and incisional treatments. However, these t 'i was not generally accepted as valid.
毛髪移植の他に、毛髪成長を刺激する最も普通のアプローチは薬剤治療の領域で あった。しかしながら、これに関する薬剤の使用は、ごく限られた成功でもって 満足されていたにすぎなかった。毛髪の成長を刺激するのに最も有望な組成物の 一つが、アップジョン社の米国特許第４．５９６．８１２号明細書に開示されて おり、これは男性のパターンはげを治療するために“ミノキシジル（Ｍｉｎｏｘ ｉｄｉｌ）”として普通知られている物質の使用を記載している。しかしながら 、ミノキシジルの使用により生じた結果は従来有望のように見えたが、温血動物 の毛髪の成長を刺激し得る改良された組成物に対する要望が当業界に依然としで ある。本発明はこの要望を満足し、更にその他の関連する利点を与える。Besides hair transplantation, the most common approach to stimulating hair growth is in the area of drug therapy. there were. However, the use of drugs in this regard has been met with only limited success. He was simply satisfied. Of the most promising compositions for stimulating hair growth One is disclosed in Upjohn's U.S. Patent No. 4.596.812. ``Minoxidil'' is used to treat pattern baldness in men. describes the use of a substance commonly known as ``idil''. However, Although the results produced by the use of minoxidil previously appeared promising, warm-blooded animals There continues to be a need in the art for improved compositions that can stimulate hair growth. be. The present invention satisfies this need and provides other related advantages.
発明の開示 簡単に言えば、本発明は活性治療物質として使用するための金属−ペプチド組成 物及びその誘導体を提供する。加えて、温血動物の毛髪の成長を刺激する薬剤の 製造に使用するための化合物が開示される。Disclosure of invention Briefly, the present invention provides metal-peptide compositions for use as active therapeutic agents. and derivatives thereof. In addition, drugs that stimulate hair growth in warm-blooded animals Compounds are disclosed for use in manufacturing.
また、本発明は、温血動物に刺激有効量の金属−ペプチド組成物または金属−ペ プチド組成物を含む製薬製剤を投与することにより温血動物の毛髪成長を刺激す る方法を提供する。The present invention also provides a stimulating effective amount of a metal-peptide composition or metal-peptide in a warm-blooded animal. Stimulating hair growth in warm-blooded animals by administering a pharmaceutical formulation comprising a putide composition provide a method for
本明細書に記載された金属−ペプチド組成物は、グリシル−し−ヒスチジル−し −リシン（ＧＨＬと称する）、Ｌ−リシル−し−ヒスチジル−グリシン（ＬＨＧ と称する）、並びにＧＨＬ及ｆｆ１ＨＧの種々の誘導体の金属イオンキレートを 含む。金属イオンは銅（ＩＩ）、カドミウム（ＩＩ）、コバルト（ＩＩ）、スズ （ＩＩ）、鉄（ＩＩ）、マンガン（ＩＩ）等を含む。こうして、銅（ＩＩ）が金 属イオンとして利用できる場合には、相当する金属−ペプチド組成物はＧａ：銅 （Ｉ Ｉ ）（ＧＨＬ−Ｃｕと称する） 、ＬＯＧ：銅（ＩＩ ＸＬＨＧ−Ｃｕ と称する）、並びにＧＨＬ−Ｃｕ及Ｕ′ＬＨＧ−Ｃｕの誘導体を含む。The metal-peptide compositions described herein are glycyl-histidyl- -lysine (referred to as GHL), L-lysyl-histidyl-glycine (LHG) ), as well as metal ion chelates of various derivatives of GHL and ff1HG. include. Metal ions include copper (II), cadmium (II), cobalt (II), and tin. (II), iron (II), manganese (II), etc. In this way, copper(II) becomes gold. When available as a genus ion, the corresponding metal-peptide composition is Ga:copper. (II) (referred to as GHL-Cu), LOG: Copper (II XLHG-Cu ), as well as derivatives of GHL-Cu and U'LHG-Cu.
ＧＨＬの金属−ペプチド誘導体は一般式［グリシル−し−ヒスチジル−し−リシ ン−Ｃｏ−Ｒコ ：Ｘを有する。Metal-peptide derivatives of GHL have the general formula [glycyl-histidyl-histidyl-lysyl] -Co-R Co:X.
（式中、Ｘは銅（１１）、カドミウム（ＩＩ）、スズ（ＩＩ）、鉄（ＩＩ）及び マンガン（ＴＩ）からなる群から選ばれた金属イオンであり、且つＲは一洲７部 分、１〜１８個の炭素原子を含むアルキル部分、６〜１２個の炭素原子を含むア リール部分、１〜１８個の炭素原子を含むアルコキシ部分、及び６〜１２個の炭 素原子を含むアリールオキシ部分、１〜１８個の炭素原子を含むアルキルアミノ 部分からなる群から選ばれ、またはＲはＬ−プロリル−し−バリル−Ｌ−フェニ ルアラニル−Ｌ−バリン、Ｌ−バリル−Ｌ−フェニルアラニル−Ｌ−バリン、Ｌ −１−リブトファン、または（グリシル）、−Ｌ−トリプトファン（式中、ｎ− １〜４）である）。(wherein, X is copper (11), cadmium (II), tin (II), iron (II) and A metal ion selected from the group consisting of manganese (TI), and R is 7 parts of Ichishu. minutes, alkyl moieties containing 1 to 18 carbon atoms, alkyl moieties containing 6 to 12 carbon atoms, a reel portion, an alkoxy portion containing 1 to 18 carbon atoms, and 6 to 12 carbon atoms. Aryloxy moiety containing elementary atoms, alkylamino containing 1 to 18 carbon atoms or R is L-prolyl-valyl-L-phenyl. Lualanyl-L-valine, L-valyl-L-phenylalanyl-L-valine, L -1-ributophane, or (glycyl), -L-tryptophan (wherein n- 1 to 4)).
ＬＨＧの金属−ペプチド誘導体は一般式：［Ｌ−リシル−し−ヒスチジル−グリ シン−〇〇−Ｒ］ ：Ｘを有する。Metal-peptide derivatives of LHG have the general formula: [L-lysyl-histidyl-glycyl] Shin-〇〇-R]: Has X.
（式中、Ｘは銅（ＩＩ）、カドミウム（ＩＩ）、コバルト（ＩＩ）、スズ（ＩＩ ）、鉄（ＩＩ）及びマンガン（ＩＩ）からなる群から選ばれた金属イオンであり 、且つＲは一間１部分、１〜１８個の炭素原子を含むアルキル部分、６〜１２個 の炭素原子を含むアリール部分、１〜１８個の炭素原子を含むアルコキシ部分、 及び６〜１２個の炭素原子を含むアリールオキシ部分、１−１８個の炭素原子を 含むアルキルアミノ部分からなる群から選ばれ、またはＲはＬ−プロリル−し− バリル−Ｌ−フェニルアラニル−Ｌ−バリン、Ｌ−バリル−Ｌ−フェニルアラニ ル−Ｌ−バリン、Ｌ−）リプトファン、または（グリシル）、−Ｌ−トリプトフ ァン（式中、ｎ＝１〜４）である）。(wherein, X is copper (II), cadmium (II), cobalt (II), tin (II) ), a metal ion selected from the group consisting of iron (II) and manganese (II). , and R is an alkyl moiety containing 1 to 18 carbon atoms, 6 to 12 an aryl moiety containing from 1 to 18 carbon atoms, an alkoxy moiety containing from 1 to 18 carbon atoms, and aryloxy moieties containing 6 to 12 carbon atoms, 1 to 18 carbon atoms selected from the group consisting of alkylamino moieties containing, or R is L-prolyl- Valyl-L-phenylalanyl-L-valine, L-valyl-L-phenylalani Lu-L-valine, L-)liptophan, or (glycyl), -L-tryptophan (in the formula, n=1 to 4).
上記の誘導体の他に、その他の化学修飾を行って金属−ペプチド組成物の生物活 性を変えることができる。例えば、グリシンは、アラニン、セリンまたはバリン を含む種々のその他のアミノ酸により置換されてもよい。更に、銅（ＩＩ）の場 合には、そのペプチドの結合親和性は、グリシンの如きＮ−末端アミノ酸を添加 して、例えば、Ｇ）Ｌ−Ｃｕをグリシル−ＧＨＬ−Ｃｕに変換することにより高 めることができる。また、ヒスチジル残基中のイミダゾール基による金属イオン に対する結合親和性は、３−メチルヒスチジンによる置換により、または別の炭 素原子を鎖に付加することによりリシル側鎖を延長することにより変性し得る。In addition to the above derivatives, other chemical modifications can be made to improve the biological activity of metal-peptide compositions. You can change your gender. For example, glycine is alanine, serine or valine. may be substituted with various other amino acids including. Furthermore, copper(II) In some cases, the binding affinity of the peptide may be improved by adding an N-terminal amino acid such as glycine. For example, by converting G)L-Cu to glycyl-GHL-Cu, You can In addition, metal ions due to the imidazole group in histidyl residues The binding affinity for It can be modified by extending the lysyl side chain by adding elementary atoms to the chain.
同様に、その他の分子、例えばヒスチジンを金属−ペプチド組成物に付加して三 成分金属−ペプチド−ヒスチジン錯体を生成できる。最後に、Ｄ−形態のアミノ 酸がＬ−形態の他に使用し得る。Similarly, other molecules, such as histidine, can be added to the metal-peptide composition to A component metal-peptide-histidine complex can be produced. Finally, the D-form amino Acids can be used in addition to the L-form.
本発明のその他の特徴は、以下の詳細な説明及び図面を参考にして明らかになる 。Other features of the invention will become apparent with reference to the following detailed description and drawings. .
顕微鏡写真である。This is a microscopic photograph.
図２は二つの注入部位に於ける促進された毛髪成長及び周囲の剃られた領域に於 （ブる毛髪成長の欠如を示すグリシル−し−ヒスチジル−Ｌ〜グリシルし−バリ ル−Ｌ−フェニルアラニルーＬ−バリン：銅（ＩＩ）溶液で注入されたマウスの 写真である。Figure 2 shows the stimulated hair growth at the two injection sites and the surrounding shaved area. (glycyl-histidyl-L to glycyl-histidyl-L indicating lack of curly hair growth) L-L-phenylalanyl-L-valine: mice injected with copper(II) solution It's a photo.
図３は注入の日から２５日目の食塩水で注入された対照マウス（左側のマウス） 及び促進された毛髪成長を示すグリシル−し−ヒスチジル−Ｌ〜グリシルし−バ リル−Ｌ−フェニルアラニルーＬ−バリン：銅（ＩＩ）溶液で注入されたマウス （右側のマウス）の写真である。Figure 3 shows a control mouse injected with saline on day 25 from the day of injection (mouse on the left). and glycyl-histidyl-L-glycyl-ba showing accelerated hair growth. Lyle-L-phenylalanyl-L-valine: mice injected with copper(II) solution (mouse on the right).
図４はグリシル−し−ヒスチジル−し−リシル−し−バリル−Ｌ−フェニルアラ ニル−Ｌ−バリン：銅（ＩＩ）で注入されたマウスからの組織部分を示す顕微鏡 写真である。Figure 4 shows glycyl-histidyl-histidyl-lysyl-valyl-L-phenylara Nyl-L-valine: Microscope showing a tissue section from a mouse injected with copper(II) It's a photo.
図５は注入後の２〜３週間以内の毛髪成長のかなりの促進を示すグリシル−Ｌ− ヒスチジルーし一すシンｎ−オクチルエステル：銅（ＩＩ）で注入されたマウス の写真である。Figure 5 shows that Glycyl-L- shows significant promotion of hair growth within 2-3 weeks after injection. Histidyl-thiosine n-octyl ester: mice injected with copper(II) This is a photo.
図６はグリシル−Ｌ−ヒスチジル−し−リシンローオクチルエステル：銅（ＩＩ ）による注入後の脂肪層の増加を示す２１日目の生体組織検査試料の顕微鏡写真 である。Figure 6 shows glycyl-L-histidyl-cy-lysine low octyl ester: copper (II Micrograph of a 21-day biopsy specimen showing an increase in the fat layer after injection with ) It is.
図７は促進された毛髪成長を示すグリシル−し−ヒスチジル−し−リシンデシル エステル：銅（ＩＩ）で注入されたマウスの写真である。Figure 7 shows glycyl-histidyl-lysine decyl showing accelerated hair growth. Ester: Photograph of a mouse injected with copper(II).
図８は促進された毛髪成長を示す領域の皮下脂肪層内の毛幹の著しい増殖を示す グリシル−し−ヒスチジル−し−リシンデシルエステル・銅（ＩＩ）で注入され たマウスから採取された生体組織検査試料の顕微鏡写真である。Figure 8 shows significant proliferation of hair shafts within the subcutaneous fat layer in areas showing accelerated hair growth. Infused with glycyl-histidyl-lysine decyl ester copper(II) This is a micrograph of a biopsy sample taken from a mouse.
図９は対照領域中の組織部分の顕微鏡写真（図９Ａ）及びグリシル−し−ヒスチ ジル−し−リシンバルミチルエステル：銅（ＩＩ）で注入されたマウスの促進さ れた毛髪成長の領域中の組織部分の顕微鏡写真（図９Ｂ）である。Figure 9 shows a micrograph of a tissue section in the control area (Figure 9A) and a glycyl-histi Dyl-thi-lysine balmityl ester: stimulation of mice injected with copper(II) FIG. 9B is a photomicrograph of a section of tissue in a region of hair growth that has been removed.
発明の詳細な説明 本明細書に記載されるＧＩＬＬ 、 ＬＨＧ及びこれらの誘導体の金属イオンキ レートは、活性治療物質として使用でき、また温血動物の毛髪成長の刺激に使用 するための薬剤の製造に使用し得る。これらの化合物を含む製薬製剤がまた開示 される。本発明の組成物は米国特許第４．７６０．０５１号、同第４．６６５． ０５４号及び同第４．８７７、７７０号明細書に詳しく記載されており、これら は参考として本明細書に含まれる。Detailed description of the invention Metal ion keys of GILL, LHG and their derivatives described herein The rate can be used as an active therapeutic substance and is also used to stimulate hair growth in warm-blooded animals. It can be used in the manufacture of drugs for Pharmaceutical formulations containing these compounds are also disclosed be done. The compositions of the present invention are described in U.S. Pat. Nos. 4.760.051 and 4.665. It is described in detail in No. 054 and Specification No. 4.877, 770, and these is included herein by reference.
Ｇｌ（Ｌの金属ペプチド誘導体は一般式％式％］： （式中、ｘは銅（ＩＩ）、カドミウム（ＩＩ）、コバルト（ＩＩ）、スズ（ＩＩ ）、鉄（ＩＩ）及びマンガン（ＩＩ）からなる群から選ばれた金属イオンであり 、且つＲは−ＮＨ，部分、１〜１８個の炭素原子を含むアルキル部分、６〜１２ 個の炭素原子を含むアリール部分、１−１８個の炭素原子を含むアルコキシ部分 、６〜１２個の炭素原子を含むアリールオキシ部分、及び１−１８個の炭素原子 を含むアルキルアミノ部分からなる群から選ばれ、またはＲはＬ−プロリル−し −バリル−Ｌ−フェニルアラニル−Ｌ−バリン、Ｌ−バリル−Ｌ−フェニルアラ ニル−Ｌ−バリン、Ｌ−トリプトファン、または（グリシル）、−Ｌ−トリプト ファン（式中、ｎ＝１〜４）である）。Gl (the metal peptide derivative of L has the general formula % formula %): (where x is copper (II), cadmium (II), cobalt (II), tin (II) ), a metal ion selected from the group consisting of iron (II) and manganese (II). , and R is -NH, a moiety, an alkyl moiety containing 1 to 18 carbon atoms, 6 to 12 Aryl moiety containing 1-18 carbon atoms, alkoxy moiety containing 1-18 carbon atoms , aryloxy moieties containing 6 to 12 carbon atoms, and 1 to 18 carbon atoms or R is selected from the group consisting of alkylamino moieties containing L-prolyl- -Baryl-L-phenylalanyl-L-valine, L-valyl-L-phenylalanyl Nyl-L-valine, L-tryptophan, or (glycyl), -L-tryptophan fan (where n=1 to 4).
ＬＨＧの金属−ペプチド誘導体は一般式：［Ｌ−リシル−し−ヒスチジル−グリ シン−〇〇−Ｒ］ ：Ｘを有する。Metal-peptide derivatives of LHG have the general formula: [L-lysyl-histidyl-glycyl] Shin-〇〇-R]: Has X.
（式中、Ｘは銅（ＩＩ）、カドミウム（ＴＩ）、コバルト（ＩＩ）、スズ（ＩＩ ）、鉄（ＩＩ）及びマンガン（ＩＩ）からなる群から選ばれた金属イオンであり 、且つＲは−ＮＨ２部分、１〜１８個の炭素原子を含むアルキル部分、６〜１２ 個の炭素原子を含むアリール部分、１−１８個の炭素原子を含むアルコキシ部分 、６〜１２個の炭素原子を含むアリールオキシ部分、１〜１８個の炭素原子を含 むアルキルアミノ部分からなる群から選ばれ、またはＲはＬ−プロリル−し−バ リル−Ｌ−フェニルアラニル−Ｌ−バリン、Ｌ−バリル−し−フェニルアラニル −し−バリン、Ｌ−トリプトファン、または（グリシル）、−Ｌ−トリプトファ ン（式中、ｎ＝１〜４）である）。(wherein, X is copper (II), cadmium (TI), cobalt (II), tin (II) ), a metal ion selected from the group consisting of iron (II) and manganese (II). , and R is an -NH2 moiety, an alkyl moiety containing 1 to 18 carbon atoms, 6 to 12 Aryl moiety containing 1-18 carbon atoms, alkoxy moiety containing 1-18 carbon atoms , aryloxy moieties containing 6 to 12 carbon atoms, containing 1 to 18 carbon atoms; or R is selected from the group consisting of alkylamino moieties consisting of Lyl-L-phenylalanyl-L-valine, L-valyl-phenylalanyl -valine, L-tryptophan, or (glycyl), -L-tryptophan (in the formula, n=1 to 4).
本発明に於いて、１：１．２：１またはそれ以下のＧＨｌ、 、ＬＨＧまたはこ れらの誘導体対金属イオンの比を使用することができる。本発明の好ましい実施 態様に於いて、ＧＨＬ 、 ＬＩＩＧまたは誘導体当たり０．５〜０．９の金属 原子の比が使用される。上記のように、好適な金属イオンは銅（ＩＩ）、カドミ ウム（ＩＩ）、コバルト（ＴＩ）、スズ（ＩＩ）、鉄（ＩＩ）、マンガン（ＩＩ ）等を含む。これらの全ての金属イオンは本発明のペプチドで錯化された場合に 活性を示すが、銅が毛髪成長の刺激に関して最高の活性を示した。In the present invention, GHl, LHG or this with a ratio of 1:1.2:1 or less Any ratio of these derivatives to metal ions can be used. Preferred implementation of the invention In embodiments, 0.5 to 0.9 metal per GHL, LIIG or derivative Atomic ratios are used. As mentioned above, suitable metal ions include copper(II), cadmium um(II), cobalt(TI), tin(II), iron(II), manganese(II) ) etc. All these metal ions when complexed with the peptides of the present invention activity, but copper showed the highest activity in stimulating hair growth.
本発明の一つの実施態様に於いて、本明細書に記載された製薬製剤は、ビヒクル ０．１ｍｌ当たり１００〜５００μｇの金属−ペプチド組成物の濃度で、好適な ビヒクルと共に、治療すべき領域に皮肉投与し得る。これに関して好適なビヒク ルは、食塩水、滅菌水、等を含む。In one embodiment of the invention, the pharmaceutical formulations described herein are A concentration of 100-500 μg of metal-peptide composition per 0.1 ml is suitable. It can be administered subcutaneously to the area to be treated with a vehicle. A suitable vehicle for this Examples include saline, sterile water, etc.
別の実施態様に於いて、Ｇ）ｆＬ 、 ＬＯＧ及びこれらの誘導体の金属イオン キレートを含む製薬製剤は、液体、ローション、クリーム、またはゲルの形態で 局所適用し得る。本発明の製薬製剤の局所投与は所定量の組成物を所望領域に直 接に適用することにより行うことができる。毛髪成長の速度を加速するのに充分 な量が有効であり、治療は毛髪成長の進行が示すかぎりしばしば繰り返すことが できる。In another embodiment, G) metal ions of fL, LOG and derivatives thereof; Pharmaceutical preparations containing chelates can be in the form of liquids, lotions, creams, or gels. May be applied topically. Topical administration of the pharmaceutical formulations of the invention involves applying a predetermined amount of the composition directly to the desired area. This can be done by applying the Enough to accelerate the speed of hair growth dosages are effective and treatments may be repeated as often as hair growth progress indicates. can.
本発明の製薬製剤の好ましい有効投薬量は約０．１重量％〜約２０重量％の金属 −ペプチド組成物の範囲であり、更に好ましい範囲は約１．０重量％〜１０．０ 重量％である。クリームまたはゲルの形態で使用され、局所適用される場合、好 適な浸透促進剤（後記される）を組成物に添加することが有益である。Preferred effective dosages of pharmaceutical formulations of the invention are from about 0.1% to about 20% metal by weight. - a range of peptide compositions, with a more preferred range being about 1.0% to 10.0% by weight. Weight%. Used in cream or gel form, preferred when applied topically It may be beneficial to add suitable penetration enhancers (described below) to the composition.
本発明の更に別の実施態様に於いて、局所適用される製薬製剤は約０．５重量％ 〜約１０重量％の乳化剤または表面活性剤を含んでもよい。ノニオン系表面活性 剤及びイオン系表面活性剤が本発明の目的に使用し得る。好適なノニオン系表面 活性剤の例は、ノニルフェノキシポリエトキシエタノール（ノンオキシツール（ ＮＯ−ｎｏｘｙｎｏｌ）−９） ＋ポリオキシエチレンオレイルエーテル（ブリ ジ（Ｂｒｉｊ）−９７）、種々のポリオキシエチレンエーテル（トリトン（Ｔｒ ｉｔｏｎｓ））、及び種々の分子量のエチレンオキサイドとプロピレンオキサイ ドのブロックコポリマー（例えば、プルロニック（Ｐｌｕｒｏｎｉｃ）６８）で ある。また、製薬上許される製剤は約１重量％〜約１０重量％の成る種のイオン 系表面活性剤を含んでもよい。これらのイオン系表面活性剤は、ノニオン系表面 活性剤に加えて、またはそれに代えて使用し得る。イオン系表面活性剤の例はラ ウリル硫酸ナトリウム及び同様の化合物を含む。In yet another embodiment of the invention, the topically applied pharmaceutical formulation contains about 0.5% by weight It may contain up to about 10% by weight of emulsifiers or surfactants. Nonionic surface activity Agents and ionic surfactants may be used for purposes of the present invention. Suitable nonionic surface An example of an activator is nonylphenoxypolyethoxyethanol (nonoxytool). NO-noxynol)-9) + polyoxyethylene oleyl ether (Brij)-97), various polyoxyethylene ethers (Triton (Tr) itons)), and ethylene oxide and propylene oxide of various molecular weights. block copolymers (e.g. Pluronic 68) be. Pharmaceutically acceptable formulations also include from about 1% to about 10% by weight of the species ions. It may also contain a surfactant. These ionic surfactants are suitable for nonionic surfaces. They may be used in addition to or in place of active agents. An example of an ionic surfactant is La Contains sodium uryl sulfate and similar compounds.
乳化剤または表面活性剤に加えて、またはこれらに代えて、局所適用される製薬 製剤は約１重量％〜約２０重量％の浸透促進剤を含んでもよい。浸透促進剤の例 はジメチルスルホキシド（ＤＭＳＯ）及び尿素である。局所適用される液体製薬 製剤の場合には、ジメチルスルホキシド（ＤＭＳＯ）の如き浸透促進剤の濃度は 製薬製剤の約３０重量％〜約８０重量％を構成し得る。Topically applied pharmaceuticals in addition to or in place of emulsifiers or surfactants The formulation may contain from about 1% to about 20% by weight of a penetration enhancer. Examples of penetration enhancers are dimethyl sulfoxide (DMSO) and urea. Topically applied liquid pharmaceuticals For formulations, the concentration of penetration enhancers such as dimethyl sulfoxide (DMSO) It may constitute from about 30% to about 80% by weight of the pharmaceutical formulation.
局所適用される製薬製剤の残りは不活性な生理学上杵される担体を含む。好適な 担体は、水、生理食塩水、細菌発育阻止食塩水（０，９■／ｍｌのベンジルアル コールを含む食塩水）、ワセリン系クリーム（ＵＳＰ親水性軟膏及び同様のクリ ーム、例えば、ユニベース（Ｕｎｉｂａｓｅ） 、パーク−デービス（Ｐａｒｋ ｅ−Ｄａｖ ｉｓ ））、種々の型の製薬上許されるゲル、並びに短鎖アルコー ル及びグリコール（例えば、エチルアルコール及びプロピレングリコール）を含 むが、これらに限定されない。The remainder of the topically applied pharmaceutical formulation includes an inert physiologically compatible carrier. suitable Carriers include water, physiological saline, and bacterial growth-inhibiting saline (0.9 μ/ml benzyl alcohol). saline solutions containing kohl), petrolatum-based creams (USP hydrophilic ointments and similar creams) For example, Unibase, Park-Davis e-Dav is)), various types of pharmaceutically acceptable gels, as well as short chain alcohols. Contains alcohols and glycols (e.g. ethyl alcohol and propylene glycol) However, it is not limited to these.
下記のものが本発明の状況内で好適な製薬製剤の例である。The following are examples of suitable pharmaceutical formulations within the context of the present invention.
製薬製剤Ａ： 金属−ペプチド組成物 ｌ０００％（ｗ／ｗ）ヒドロキシルエチルセルロース ３．０％プロピレングリコール ２０．０％ ノンオキシノ−ルー９ ３．０％ ラウリル硫酸ナトリウム ２．０％ ベンジルアルコール ２．０％ ０．２Ｎのリン酸緩衝液 ６０．０％ 製薬製剤Ｂ： 金属−ペプチド組成物 １０．０％（Ｗ／Ｗ）ノンオキシノ−ルー９ ３．０％ エチルアルコール ８７．０％ 製薬製剤Ｃ： 金属−ペプチド組成物 ５．０％（ｗ／ｖ）エチルアルコール ４７．５％ イソプロピルアルコール ４．０％ プロピレングリコール ２０．０％ ラオネス（Ｌａｏｎｅｔｈ）−４１，０％水 ２２．５％ 製薬製剤Ｄり 金属−ペプチド組成物 ５．０％（ｗ／ｖ）滅菌水 ９５．０％ 製薬製剤Ｅ： 金属−ペプチド組成物 ５．０％（ｗ／ｖ）ヒドロキシプロピルセルロース ２ ．０％グリセリン ２０．０％ ノンオキシノ−ルー９ ３．０％ 滅菌水 ７０．０％ 製薬製剤Ｆ・ 金属−・ペプチド組成物 １．０％（ｗ／ｗ）ノンオキシノ−ルー９ ５．０％ ユニベースクリーム ９４．０％ 本明細書に記載された誘導体の使用が図１に示され、これは促進された毛髪成長 の領域の組織を示す顕微鏡写真である。更に詳しくは、図１に示されるように、 上置１２ （暗い物体）１２は、毛細血管１６により囲まれた大きな皮下脂肪細 胞１４（白い丸形の細胞）の厚い領域（ｈｅａｖｙ ｆｉｅｌｄ）に埋め込まれ ている。増大された毛髪成長と関連する領域中の皮下脂肪の強化（脂肪細胞形成 ）は非常に重要である。Pharmaceutical formulation A: Metal-peptide composition l000% (w/w) hydroxyl ethyl cellulose 3.0% propylene glycol 20.0% Non-oxygenol 9 3.0% Sodium lauryl sulfate 2.0% Benzyl alcohol 2.0% 0.2N phosphate buffer 60.0% Pharmaceutical formulation B: Metal-peptide composition 10.0% (W/W) Nonoxyno-9 3.0% Ethyl alcohol 87.0% Pharmaceutical formulation C: Metal-peptide composition 5.0% (w/v) Ethyl alcohol 47.5% Isopropyl alcohol 4.0% Propylene glycol 20.0% Laoneth - 41.0% water 22.5% Pharmaceutical preparation D Metal-peptide composition 5.0% (w/v) Sterile water 95.0% Pharmaceutical formulation E: Metal-peptide composition 5.0% (w/v) hydroxypropylcellulose 2 ．． 0% glycerin 20.0% Non-oxygenol 9 3.0% Sterilized water 70.0% Pharmaceutical preparation F・ Metal-peptide composition 1.0% (w/w) Non-oxyno-9 5.0% Unibase Cream 94.0% The use of the derivatives described herein is illustrated in Figure 1, which promotes hair growth. FIG. More specifically, as shown in Figure 1, Upper part 12 (dark object) 12 is a large subcutaneous fat thin tissue surrounded by capillaries 16. Embedded in the heavy field of cell 14 (white round cell) ing. Enhancement of subcutaneous fat in areas associated with increased hair growth (adipocyte formation) ) is very important.
増大された脂肪細胞形成は上置形成と空間的且つ一時的に関連しており、上置形 成の不可欠な段階である（Ｈａｕｓｍａｎら、Ａｎ Ｊ、 Ａｎａｔ、 １６１ ：８５−１００． ］ ９８１ ）。更に、男性のパターンはげは非生産的で ある上置と密接な関連がある。逆に、哺乳類の迅速な毛髪成長の期間中では、皮 下脂肪含量は２倍〜３倍に増加する。Enhanced adipogenesis is spatially and temporally associated with epiplasia; (Hausman et al., An J, Anat, 161 :85-100. ] 981). Additionally, pattern baldness in men is counterproductive. It is closely related to certain superpositions. Conversely, during periods of rapid hair growth in mammals, the skin Lower fat content increases 2-3 times.
それ故、本発明の誘導体は少なくとも三つの主要な領域、即ち、（１）脱毛の個 人の毛髪成長の直接の刺激、（２）毛髪移植体の刺激、及び（３）皮下脂肪含量 の増大に臨床りの用途を有する。Therefore, the derivatives of the present invention can be used in at least three major areas, namely: (1) the individuality of hair loss; Direct stimulation of human hair growth, (2) stimulation of hair transplants, and (3) subcutaneous fat content. It has clinical use in increasing the
上記のように、本発明の組成物はＧＨＬ 、ＩＪＩＧまたはこれらの誘導体の金 属イオンキレートを含む。ＧＨＬ誘導体の合成に於ける全化学反応は、次式のよ うに表し得る。As mentioned above, the compositions of the present invention contain gold of GHL, IJIG or their derivatives. Contains genus ion chelates. The entire chemical reaction in the synthesis of GHL derivatives is as follows: It can be expressed as a sea urchin.
ＧＨＬ〜ＯＨ＋Ｒ−Ｈ＞ＧＨＬ−Ｒ＋Ｈ２０その反応は、リシンとその他の二種 のアミノ酸を組み合わせてＧＨＬとする前にＲ基をアミノ酸リジンに付加するこ とにより最も容易に行われる。ＧＨＬ−Ｒの生成及び単離後に、金属イオンがそ の分子に錯化されて生物活性錯体を生成する。GHL~OH+R-H>GHL-R+H20The reaction is between ricin and two other species. Adding an R group to the amino acid lysine before combining the amino acids to form GHL. This is most easily done by After generation and isolation of GHL-R, metal ions are removed from it. molecules to form biologically active complexes.
ＧＨＬ−Ｘ（式中、Ｘは金属イオンである）の更に脂質親和性の誘導体を生成す るための全反応は、下記の式のように表し得る。Further lipophilic derivatives of GHL-X (wherein X is a metal ion) are produced. The overall reaction for this can be expressed as follows:
１辺シン−ＯＨ＋Ｒ−Ｈ−−一−＞リシン−Ｒ＋Ｈ２Ｏ２辺シン−Ｒ＋ブロック されたし一ヒスチジンー・−〉ブロックされたし一ヒスチジンーし一すシンーＲ ３）ブロックされたし一ヒスチジンーし一すシンーＲ−−−−〉部分ブロックさ れたし一ヒスチジンーし一すシンーＲ ４）部分ブロックされたし一ヒスチジンーＬ−リシンーＲ＋ブロックされたグリ シン、−〉ブロックされたグリシル−し−ヒスチジン−し−リシン−Ｒ５）ブロ ックされたグリシル−し−ヒスチジン−し−リシン−Ｒ−−−−＞グリシル−し −ヒスチジン−し−リシン−Ｒ６）グリシル−し−ヒスチジン−し−リシン−Ｒ ＋Ｘ−−＞グリシル−し−ヒスチジン−し−リシン−Ｒ：ＸＬＨＧ−Ｘの誘導体 を生成するための全反応は、リシン−ＯＨに代えてグリシン−ＯＨが初期の反応 成分であり、ブロックされたりシンが工程４でブロックされたグリシンに代えて 使用される以外は、ＧＨＬ−Ｘに関して上記されたものと同じである。1 side thin-OH+R-H--1->Ricine-R+H2O2 side thin-R+block Blocked one histidine --> Blocked one histidine -- R 3) Blocked one-histidine-one-histidine-R---->partial block Histidine Histidine R 4) Partially blocked histidine-L-lysine-R+blocked lysine Syn, -〉Blocked glycyl-cy-histidine-cy-lysine-R5) Checked glycyl-shi-histidine-shi-lysine-R--->glycyl-shi -histidine-shi-lysine-R6) glycyl-shi-histidine-shi-lysine-R +X-->glycyl-histidine-lysine-R: derivative of XLHG-X The entire reaction to produce lysine-OH is replaced by glycine-OH in the initial reaction. component, blocked or syn is substituted for the blocked glycine in step 4. The same as described above for GHL-X except that it is used.
以下の実施例を要約すると、実施例１〜５はＧＨＬ誘導体の合成を示す。実施例 １はグリシル−し−ヒスチジル−し−リシンベンジルエステル：銅（ＩＩ）の合 成である。To summarize the examples below, Examples 1-5 demonstrate the synthesis of GHL derivatives. Example 1 is a synthesis of glycyl-histidyl-lysine benzyl ester: copper(II) It is complete.
実施例２はグリシル−し−ヒスチジル−し−リシンｎ−オクチルエステル：銅（ ＩＩ）の合成を示す。実施例３はグリシル−し−ヒスチジル−し−リシンｎ−ス テアリルエステル・銅（ＴＩ）の合成を示す。この操作に基いて、当業者はｎ− ステアリルアルコール（１８個の炭素）に代えてｎ−パルミチルアルコール（１ ６個の炭素）を使用してグリシル−し−ヒスチジル−し−リシンｎ一式ルミチル ・銅（ＩＩ）を生成し得る。実施例４はグリシル−し−ヒスチジル−し−リシル −し−プロリル−し−フェニルアラニル−Ｌ−バリン：銅（ＩＩ）及びグリシル −し−ヒスチジル−し−リシル−し−バリル−Ｌ−フェニルアラニル−Ｌ−バリ ン：銅（Ｉｉ）の合成を示す。実施例５はＬ−リシル−し−ヒスチジル−グリシ ンｎ−オクチルアミドの合成を示す。Example 2 is glycyl-histidyl-lysine n-octyl ester: copper ( The synthesis of II) is shown. Example 3 is glycyl-histidyl-lysine n-su The synthesis of thearyl ester copper (TI) is shown. Based on this operation, a person skilled in the art would know that n- Stearyl alcohol (18 carbons) was replaced with n-palmityl alcohol (1 6 carbons) using glycyl-histidyl-lysine n set lumityl - Can produce copper (II). Example 4 is glycyl-histidyl-lysyl -prolyl-phenylalanyl-L-valine: copper(II) and glycyl -Histidyl-S-lysyl-S-Valyl-L-phenylalanyl-L-Vari N: Shows the synthesis of copper (Ii). Example 5 is L-lysyl-histidyl-glycyl 1 shows the synthesis of n-octylamide.
実施例６〜９はＬＯＧ及びその誘導体の合成を示す。実施例６はＬ−リシル−し −ヒスチジル−グリシンアミドの合成を示す。実施例７はＬ−リシル−し−ヒス チジル−グリシンアミドの合成を示す。実施例８はオクチルし一リシルーし一ヒ スチジルーグリシネートの合成を示す。実施例９はＬ−リシル−し−ヒスチジル −グリシル−１−ｔ＜リルーし一フェニルアラニルーＬ−バリンのマルチグラム 合成を示す。Examples 6-9 demonstrate the synthesis of LOG and its derivatives. Example 6 is L-lysyl -Synthesis of histidyl-glycinamide is shown. Example 7 is L-lysyl-his 1 shows the synthesis of tidyl-glycinamide. Example 8 is octyl, one lysyl, one h 1 shows the synthesis of stidylglycinate. Example 9 is L-lysyl-histidyl - Multigram of glycyl-1-t<re-1-phenylalanyl-L-valine Showing synthesis.
実施例１Ｏはグリシル−し−ヒスチジル−し−リシル−し−バリル−Ｌ−フェニ ルアラニル−Ｌ−バリン・銅（ＩＩ）によるマウスに於ける刺激され、促進され た毛髪成長を示す。実施例１１は種々の金属イオンと錯生成されたグリシル−し −ヒスチジル−し−リシンｎ−オクチルエステルにより刺激され、促進された毛 髪成長を示す。実施例１２はＬ−リシル−し−ヒスチジルーグリシンオクチルエ ステル・銅（ＩＩ）及びＬ−リシル−Ｌ−ヒスチジル−グリシル−Ｌ−バリル− Ｌ−フェニルアラニル−Ｌ−バリン・銅（ＩＩ）による毛髪成長の刺激及び促進 を示す。実施例１３はグリシル−し−ヒスチジル−Ｌ−リシル−し−バリル−Ｌ −フェニルアラニル−バリン：銅（ＩＩ）の局所適用により刺激され、促進され た毛髪成長を示す。実施例１４はグリシル−１，−（３−メチル）−ヒスチジル −Ｉ、−リシル−Ｌ−グリシル−Ｌ−トリプトファンによる毛髪成長の刺激及び 促進を示す。実施例１５はグリシル−し−ヒスチジル−Ｌ−リシンｎ−オクチル エステル：銅（ＩＩ）による毛髪成長の刺激及び促進を示す。実施例１６はグリ シル−し−ヒスチジル−Ｌ−リシンデシルエステル、銅（ＩＩ）による毛髪成長 の刺激及び促進を示す。実施例１７はグリシル−し−ヒスチジル−し−リシンバ ルミチルエステル：銅（ＩＩ）による毛髪成長の刺激及び促進を示す。Example 1O is glycyl-histidyl-histidyl-lysyl-valyl-L-phenylene. lualanyl-L-valine stimulated and promoted in mice by copper(II) Shows increased hair growth. Example 11 shows glycyl complexed with various metal ions. - Hair stimulated and promoted by histidyl-lysine n-octyl ester Showing hair growth. Example 12 is L-lysyl-histidyl-glycine octyle Stell copper(II) and L-lysyl-L-histidyl-glycyl-L-valyl- Stimulation and promotion of hair growth with L-phenylalanyl-L-valine/copper(II) shows. Example 13 is glycyl-histidyl-L-lysyl-valyl-L -Phenylalanyl-valine: stimulated and promoted by topical application of copper(II) Shows increased hair growth. Example 14 is glycyl-1,-(3-methyl)-histidyl -I, -lysyl-L-glycyl-L-tryptophan stimulation of hair growth and Show facilitation. Example 15 is glycyl-histidyl-L-lysine n-octyl Ester: Indicates stimulation and promotion of hair growth by copper(II). Example 16 is Hair growth with sil-histidyl-L-lysine decyl ester, copper(II) Indicates stimulation and promotion of Example 17 is glycyl-histidyl-lysymba Lumityl Ester: Indicates stimulation and promotion of hair growth by copper(II).
以下の実施例は説明のために示されるものであり、本発明を限定するためのもの ではない。The following examples are given by way of illustration and are not intended to limit the invention. isn't it.
上記の実施例に使用した薬品及びペプチド中間体は幾つかの供給業者、例えばシ グマ・ケミカル社（ミズーリイ州、セントルイス）、ペニンスラ・ラボラトリイ ズ社（カリフォルニア州、サンカルロス）、アルドリッジ・ケミカル社（ウィス コンシン州、ミルウォーキイ）、ベガ・バイオケミカルズ社（アリシナ州、タク ソン）、ピアス・ケミカル社（イリノイ州、ロックフォード）、リサーチ・ノく イオケミカルズ社（オハイオ州、クレーブランド）、パン・ウォーターズ・アン ド・ロジャース社（カリフォルニア州、サウスサンフランシスコ）、ベーケム社 （カリフォルニア州、トランス）から購入し得る。The drugs and peptide intermediates used in the examples above are available from several suppliers, e.g. Guma Chemical Company (St. Louis, Missouri), Peninsula Laboratory (San Carlos, California), Aldridge Chemical Company (Wis. (Milwaukee, Consin); Vega Biochemicals (Tac., Alicina); Pierce Chemical Company (Rockford, Illinois), Research No. Iochemicals (Cleveland, Ohio), Pan Waters Anne de Rogers Company (South San Francisco, California), Bechem Company (California, Torrance).
ペプチド及びペプチド類縁体の金属錯体の調製ＧＨＬ 、 ＬＧＨ及びこれらの 誘導体の金属錯体は、蒸留水中の溶液のＧＨＬ 、 ＬＧＨまたはこれらの誘導 体に、必要とされるモル量の超純粋金属塩化物（例えば、ニュージャーシイ州に あるケミカル・ダイナミクス社から入手し得る９９．９９９％のもの）を添加す ることによりあらゆるモル比で調製し得る。金属塩化物の添加後に、溶液のｐＨ をほぼ中性に調節する。生成した沈殿は通常の手段により遠心分離及び濾過によ り除去し得る。また、塩化物以外の金属塩、例えば、酢酸塩、硫酸塩、または硝 酸塩が使用し得る。Preparation of metal complexes of peptides and peptide analogs GHL, LGH and their Derivative metal complexes are GHL, LGH or their derivatives in solution in distilled water. body with the required molar amount of ultrapure metal chloride (e.g. 99.999% available from Chemical Dynamics, Inc.). Any molar ratio can be prepared by After adding the metal chloride, the pH of the solution Adjust to almost neutral. The generated precipitate is centrifuged and filtered by conventional means. can be removed. Also, metal salts other than chlorides, such as acetates, sulfates, or nitrates, Acid salts may be used.
Ｎｏ−ベンジルオキシカルボニル−し−リシンベンジルエステルを１＝１のヘキ サン−酢酸エチルに溶解し、カップリング剤としてジシクロへキシルカルボジイ ミドを使用してＮ”＋ブチルオキシカルボニルーＮ’″−ベンジルオキシカルボ ニル−し−ヒスチジンにカップリングさせた。重炭酸ナトリウム（１０％）を添 加し、生成物を有機層に抽出した。生成物、Ｎ”−ドブチルオキシカルボニル− Ｎ１ｍ−ベンジルオキシカルボニル−し−ヒスチジル−Ｎ１−ベンジルオキシカ ルボニル−１，−リシンベンジルエステルを溶液から結晶化させた。ブロックさ れたジペプチドのＮ−末端基を、ジクロロメタン中５０％のトリフルオロ酢酸中 で３０分間攪拌することにより除去し、次いで減圧で蒸発させた。No-benzyloxycarbonyl-lysine benzyl ester with 1=1 hexyl dicyclohexylcarbodiyl as a coupling agent, dissolved in ethyl acetate. N”+butyloxycarbonyl-N’”-benzyloxycarbo using mido Coupled to nyl-histidine. Added sodium bicarbonate (10%) and the product was extracted into the organic layer. Product, N”-dobutyloxycarbonyl- N1m-benzyloxycarbonyl-histidyl-N1-benzyloxycarbonyl Rubonyl-1,-lysine benzyl ester was crystallized from solution. block The N-terminal group of the dipeptide was dissolved in 50% trifluoroacetic acid in dichloromethane. was removed by stirring for 30 minutes at 1000 ml and then evaporated under reduced pressure.
生成物、Ｎ１１ｌ−ベンジルオキシカルボニル−し−ヒスチジル−Ｎｏ−ベンジ ルオキシカルボニル−し−リシンベンジルエステルをカップリング剤としてジシ クロへキシルカルボジイミドを使用してｔ−ブチルオキシカルボニル−し−グリ シンにカップリングさせた。ブロッキング基を氷酢酸中で１０％のパラジウム／ カーボンを使用して接触水素化により除去した。凍結乾燥後に、生成物、グリシ ル−し−ヒスチジル−し−リシンベンジルエステルを水に溶解し、ダウエックス （Ｄｏｗｅｘ）４０Ｘ−４陽イオン交換樹脂によるイオン交換クロマトグラフィ ー及び０．１Ｍの水酸化アンモニウムによる溶離により精製し、溶離液を直ちに 酢酸で中和した。更に中性ｐＨで陰イオン交換カラムバイオレックス（ＢｉｏＲ ｅｘ）６３に通して、遊離カルボン酸基を有する分解生成物を除去した。Product, N11l-benzyloxycarbonyl-histidyl-No-benzi lysine benzyl ester as a coupling agent. t-Butyloxycarbonyl glycol using chlorhexylcarbodiimide Coupled with Shin. Blocking groups were removed with 10% palladium/chloride in glacial acetic acid. It was removed by catalytic hydrogenation using carbon. After lyophilization, the product, glycine Dissolve ru-histidyl-lysine benzyl ester in water and use Dowex. (Dowex) Ion exchange chromatography using 40X-4 cation exchange resin - and 0.1 M ammonium hydroxide, and the eluent was immediately washed away. Neutralized with acetic acid. Furthermore, an anion exchange column BioRex (BioR) was used at neutral pH. ex) 63 to remove decomposition products with free carboxylic acid groups.
グリシル−し−ヒスチジル−し−リシンベンジルエステルを水に溶解し、等モル の酢酸銅（ＩＩ）を添加した。ｐＨを水酸化ナトリウムで中性まで上げた。その 溶液を３℃で１時間にわたって２０．０００ｘｇで遠心分離して難溶性物質を除 去した。上澄み液を凍結乾燥してグリシル−し−ヒスチジルルーリシンベンジル エステル：銅（ＩＩ）を得た。Glycyl-histidyl-lysine benzyl ester is dissolved in water and equimolar of copper(II) acetate was added. The pH was raised to neutral with sodium hydroxide. the The solution was centrifuged at 20,000 x g for 1 hour at 3 °C to remove poorly soluble materials. I left. Freeze-dry the supernatant to obtain glycyl-histidyl luricin benzyl. Ester: copper (II) was obtained.
Ｎｏ−ベンジルオキシカルボニル−し−リシン、ｎ−オクタツール、ベンセン、 及びｐ−）ルエンスルホン酸−水和物の混合物を、ディージ・スタークトラップ を使用して一夜還流させて水を除去した。冷却後、乾燥エチルエーテルを添加し た。No-benzyloxycarbonyl-lysine, n-octatool, benzene, and p-) luenesulfonic acid-hydrate in a Digi-Stark trap. The water was removed by refluxing overnight using a After cooling, add dry ethyl ether Ta.
次いで、その溶液を０℃で一夜にわたって沈殿させた。沈殿した固体の一部を炭 酸カリウム溶液５０ｍ１及びジクロロメタン５０ｍ１に添加した。抽出後、層を 分離し、有機相を水洗し、食塩水で洗浄し、次いで無水硫酸マグネシウムで乾燥 させた。The solution was then allowed to precipitate overnight at 0°C. Charcoal some of the precipitated solids 50 ml of potassium acid solution and 50 ml of dichloromethane were added. After extraction, the layer Separate and wash the organic phase with water, brine, and then dry over anhydrous magnesium sulfate. I let it happen.
濾過し、蒸発させ、フラッシュカラムクロマトグラフィーにより精製してｎ−オ クチルＮ０−ベンジルオキシカルボニル−し−リシンを得た。Filter, evaporate and purify by flash column chromatography to obtain n-o Cutyl NO-benzyloxycarbonyl-cyclolysine was obtained.
その生成物をテトラヒドロフランに溶解し、Ｎ“−ｔ−ブチルオキシカルボニル −Ｎｕｍ−ベンジルオキシカルボニル−し−ヒスチジン、イソブチルクロロホル メート及の一メチルモルホリンと混合した。蒸発後、水及び酢酸エチルを添加し た。その生成物を有機相に抽出し、これを無水硫酸マグネシウムで乾燥させた。The product was dissolved in tetrahydrofuran and N“-t-butyloxycarbonyl -Num-benzyloxycarbonyl-histidine, isobutylchloroform Mixed with mate and one methylmorpholine. After evaporation, add water and ethyl acetate Ta. The product was extracted into the organic phase, which was dried over anhydrous magnesium sulfate.
濾過し、蒸発させ、フラッシュカラムクロマトグラフィーにより精製してｎ−オ クチルＮ１−ｔ−ブチルオキシカルボニル＝Ｎ′１−ベンジルオキシカルボニル −Ｌ−ヒスチジル−Ｎ“−ベンンルオキシカルボニルーＬ−リシネートを得た。Filter, evaporate and purify by flash column chromatography to obtain n-o Cutyl N1-t-butyloxycarbonyl=N'1-benzyloxycarbonyl -L-Histidyl-N''-bennylooxycarbonyl-L-ricinate was obtained.
その生成物をジクロロメタン中の５０％のトリフルオロ酢酸に３０分間で溶解し 、次いで蒸発させて、ｎ−オクチルＮ１″′−ベンジルオキシカルボニル−し− ヒスチジル−Ｎ”−ベンジルオキシカルボニルーし一すシネートを生成した。こ れをテトラヒドロフランに溶解し、イソブチルクロロホルメート、Ｎ−メチルモ ルホリン及びベンジルオキシカルボニルグリシンを添加してｎ−オクチルベンン ルオキシ力ルポニルグリンル−Ｎｏ１−ベンジルオキシカルボニル−し−ヒスチ ジル−Ｎ’−ヘンシルオキシカルボニル−１７−リンネートを生成した。これを 氷酢酸に溶解し、−夜にわたつて水素化した。The product was dissolved in 50% trifluoroacetic acid in dichloromethane for 30 minutes. , then evaporated to give n-octylN1″'-benzyloxycarbonyl- Histidyl-N''-benzyloxycarbonyl-cysinate was produced. Dissolve this in tetrahydrofuran, add isobutyl chloroformate, N-methyl chloroformate, n-octylbenzene by adding luforin and benzyloxycarbonylglycine Benzyloxycarbonyl-No1-benzyloxycarbonyl-histi Dyl-N'-hensyloxycarbonyl-17-phosphate was produced. this Dissolved in glacial acetic acid and hydrogenated overnight.
得られたグリシル−し−ヒスチジル−し−リジンのｎ−オクチルエステルを、水 に溶解し、等モル量の酢酸第二銅と混合することにより銅（ＩＩ）錯体に変換し た。ｐＨを水酸化ナトリウムで中性まで上げた。その溶液を３℃で１時間にわた って２０．０００Ｋｇで遠心分離して難溶性物質を除去した。上澄み液を凍結乾 燥してグルシル−Ｌ−ヒスチジル−Ｌ−リシンベンジルオクチル：銅（ＩＩ）を 得た。The obtained n-octyl ester of glycyl-histidyl-lysine was dissolved in water. It is converted to a copper(II) complex by dissolving it in Ta. The pH was raised to neutral with sodium hydroxide. The solution was heated at 3℃ for 1 hour. The mixture was centrifuged at 20,000 kg to remove poorly soluble substances. Freeze-dry the supernatant Glucyl-L-histidyl-L-lysinebenzyloctyl:copper(II) was dried. Obtained.
実施例３ グリシル−し−ヒスチジル−し−リシンｎ−ステアリルエステル：銅（Ｉｌ）の 合成Ｎ＠−ベンジルオキシカルボニル−し−リジン、ｎ−ステアリルアルコール 、ベンセン、及びｌ）−トルエンスルホン酸−水和物の混合物を、ディージ・ス タークトラップを使用して一夜還流させて発生する水を共沸により除去した。室 温に冷却し、次いで乾燥エチルエーテルを添加した後、ｎ−ステアリルＮ１−ベ ンジルオキシカルボニル−し−リンネートり−）ルエンスルホン酸塩を濾過によ り回収し、２Ｍの重炭酸カリウム水溶液で処理し、ジクロロメタンで抽出した。Example 3 Glycyl-histidyl-lysine n-stearyl ester: Copper(Il) Synthesis N@-benzyloxycarbonyl-lysine, n-stearyl alcohol , benzene, and l)-toluenesulfonic acid-hydrate were added to The resulting water was azeotropically removed by refluxing overnight using a turk trap. room After cooling to room temperature and adding dry ethyl ether, the n-stearyl N1-beta (dioxycarbonyl-phosphorus-)luenesulfonate by filtration. Collected by filtration, treated with 2M aqueous potassium bicarbonate and extracted with dichloromethane.
蒸発させて遊離アミンを得、これを乾燥テトラヒドロフラン（ＴＩ（Ｆ）に再度 溶解し、−１５℃で乾燥１中のＮ“−ｔ−ブチルオキシカルボニル−Ｎ１″−ベ ンジルオキシカルボニル−し−ヒスチジン、Ｎ−メチルモルホリン、及びイソブ チルクロロホルメートの攪拌溶液に添加した。Evaporation gave the free amine, which was redissolved in dry tetrahydrofuran (TI(F)). Dissolve and dry at -15°C N"-t-butyloxycarbonyl-N1"-beta in 1. N-methyloxycarbonyl-histidine, N-methylmorpholine, and isobutylene Added to stirred solution of methyl chloroformate.
得られる充分に保護されたジペプチドエステルを室温でｌ／ｌのトリフルオロ酢 酸／ジクロロメタンで処理し、飽和重炭酸ナトリウム水溶液で中和し、酢酸エチ ルで抽出する。蒸発させて部分脱ブロックされたジペプチドを得、これを乾燥Ｔ ＨＦに再度溶解し、−１５℃で乾燥ＴＨＦ中のベンジルオキシカルボニルグリシ ン、Ｎ−メチルモルホリン及びイソブチルクロロホルメートの攪拌溶液に添加す る。生成した充分に保護されたトリペプチドエステルを氷酢酸中で室温でＰｄ− Ｃ触媒の存在下で水素ガスによる処理により完全に脱ブロックする。濾過し、蒸 発させ、微結晶性セルロースカラムで精製し、続いて凍結乾燥して所望のトリペ プチドをその三酢酸塩として得た。The resulting fully protected dipeptide ester was dissolved in l/l trifluoroacetic acid at room temperature. Treat with acid/dichloromethane, neutralize with saturated aqueous sodium bicarbonate solution, and evaporate with ethyl acetate. Extract with file. Evaporation yields a partially deblocked dipeptide, which is dried T Benzyloxycarbonylglycide in THF was redissolved in HF and dried at -15 °C. When added to a stirred solution of N-methylmorpholine and isobutyl chloroformate, Ru. The resulting fully protected tripeptide ester was dissolved in glacial acetic acid at room temperature by Pd- Complete deblocking is achieved by treatment with hydrogen gas in the presence of C catalyst. filtered and steamed The desired tripeptide Putido was obtained as its triacetate salt.
得られた分子、グリシル−し−ヒスチジル−し−リシンのローステアリルエステ ルを水に溶解し、等モル量の酢酸第二銅と混合することにより銅（ＩＩ）錯体に 変換した。The resulting molecule, low-stearyl ester of glycyl-histidyl-lysine Copper(II) complexes are prepared by dissolving the copper(II) complex in water and mixing with an equimolar amount of cupric acetate. Converted.
ｐＨを水酸化ナトリウムで中性まで上げた。その溶液を３℃で２０．０００Ｘｇ で１時間遠心分離して難溶性物質を除去した。上澄み液を凍結乾燥してグリシル −し−ヒスチジル−し−リシンベンジルステアリル：銅（ＩＩ）を得た。The pH was raised to neutral with sodium hydroxide. 20.000Xg of the solution at 3℃ The mixture was centrifuged for 1 hour to remove poorly soluble substances. Freeze-dry the supernatant to make glycyl -Histidyl-lysinebenzylstearyl: copper(II) was obtained.
ｎ−ステアリルアルコールをｎ−パルミチルアルコールに置換することにより、 グリシル−し−ヒスチジル−し−リシンｎ−パルミチルエステルを同様にして合 成し得る。By replacing n-stearyl alcohol with n-palmityl alcohol, Glycyl-histidyl-lysine n-palmityl ester was synthesized in the same manner. It can be accomplished.
実施例４ グリシル−し−ヒスチジル−し−リシル−し−プロリル−し−バリル−Ｌ−フェ ニルアラニル−Ｌ−バリン 銅（ＩＩ）及びグリシル−し−ヒスチジル−Ｌ−リ シル−Ｌ−７クリルーＬ−フェニルアラニル−Ｌ−バリン：銅（ＩＩ）の合成α 窒素のためのｔ−ブチルオキシカルボニル保護基、側鎖保護のためのベンジルオ キシカルボニル保護基及びカップリングのための混合酸無水物法を使用する通常 の溶液相法によりマルチグラム（ｍｕｌｔｉ−ｇｒａｍ）量のグリシル−し−ヒ スチジル−Ｌ−リシル−し−バリル−Ｌ−フェニルアラニル−Ｌ−バリンを合成 した。簡単に言えば、Ｌ−バリンベンジルエステルｐ−スルホン酸塩を、カップ リング剤としてイソブチルクロロホルメート及びトメチルモルホリンを使用して ｔ−ブチルオキシカルボニル−し−フェニルアラニンとカップリングした（−２ ０℃で２時間、次いで周囲温度で１時間）。次いでジペプチドのｔ−ブチルオキ シカルボニル保護基をジクロロメタン中３０％のトリフルオロ酢酸により室温で ３０分間で除去した。所望のペプチドを得るため、ブロックされたアミノ酸（ｔ −ブチルオキシカルボニル−Ｌ−バリン、Ｎ１−１−ブチルオキシカルボニル− Ｎ１−ベンジルオキシカルボニル−し−リシン、Ｎ”−ドブチルオキシカルボニ ル−Ｎ１ｍ−ベンジルオキシカルボニル−し−ヒスチジン、ペンジルオキシ力ル ボニルグ１ルン）を添加し、ｔ−ブチルオキシカルボニル保護基を逐次除去した 。１０％Ｐｄ−Ｃ触媒の存在下で５日間にわたって酢酸中で水素を使用して最終 ペプチドを完全に脱保護した。最終ペプチドを水から凍結乾燥し、Ｃ−１８逆相 カラムによる液体クロマトグラフィーにより精製して所望のへキサペプチドをマ ルチグラム量で生成した。Example 4 glycyl-histidyl-lysyl-prolyl-valyl-L-phene Nylalanyl-L-valine Copper(II) and glycyl-histidyl-L-valine Sil-L-7 Krylu L-phenylalanyl-L-valine: Synthesis α of copper(II) t-butyloxycarbonyl protecting group for nitrogen, benzyloxycarbonyl protecting group for side chain protection Typically using a xycarbonyl protecting group and a mixed anhydride method for coupling multi-gram quantities of glycyl Synthesis of stidyl-L-lysyl-valyl-L-phenylalanyl-L-valine did. Briefly, L-valine benzyl ester p-sulfonate is Using isobutyl chloroformate and tomethylmorpholine as ring agents Coupled with t-butyloxycarbonyl-phenylalanine (-2 2 hours at 0°C then 1 hour at ambient temperature). Then the dipeptide t-butyloxy The cyclocarbonyl protecting group was removed with 30% trifluoroacetic acid in dichloromethane at room temperature. It was removed in 30 minutes. To obtain the desired peptide, blocked amino acids (t -Butyloxycarbonyl-L-valine, N1-1-butyloxycarbonyl- N1-benzyloxycarbonyl-lysine, N”-dobutyloxycarbonyl -N1m-benzyloxycarbonyl-histidine, penzyloxycarbonyl carbonyl group) was added and the t-butyloxycarbonyl protecting group was sequentially removed. . The final reaction was carried out using hydrogen in acetic acid for 5 days in the presence of 10% Pd-C catalyst. The peptide was completely deprotected. The final peptide was lyophilized from water and C-18 reverse phase The desired hexapeptide is purified by liquid chromatography using a column. produced in multigram amounts.
得られるヘキサペプチドグリシル−し−ヒスチジル−し−リシル−１−／（リル −Ｌ−フェニルアラニル−Ｌ−バリンを、水に溶解し、等モル量の酢酸第二銅と 混合することにより銅（ＩＩ）錯体に変換した。ｐＨを水酸化ナトリウムで中性 まで上げた。その溶液を３℃で２０．０００Ｘｇで１時間遠心分離して難溶性物 質を除去した。上澄み液を凍結乾燥してグリシル−し−ヒスチジル−し−リシル −Ｌ−バリルルーフェニルアラニル−Ｌ−バリン：銅（ＩＩ）を得た。The resulting hexapeptide glycyl-histidyl-lysyl-1-/(lyl) -L-phenylalanyl-L-valine is dissolved in water, and an equimolar amount of cupric acetate is added to the solution. By mixing, it was converted into a copper(II) complex. Neutralize pH with sodium hydroxide I raised it to The solution was centrifuged at 20,000×g for 1 hour at 3°C to remove hardly soluble substances. quality was removed. Lyophilize the supernatant to give glycyl-histidyl-lysyl. -L-valyl-phenylalanyl-L-valine: copper(II) was obtained.
同様の合成に於いて、α窒素のためのｔ−ブチルオキシカルボニル保護基、側鎖 保護のためのベンジルオキシカルボニル基及びカップリングのための混合酸無水 物法を使用する通常の溶液相法によりマルチグラム量のグリシル−Ｌ−ヒスチジ ル−し−リシル−し−プロリル−１，−バリル−Ｌ−フェニルアラニル−し−バ リンを合成した。In a similar synthesis, a t-butyloxycarbonyl protecting group for the alpha nitrogen, a side chain Benzyloxycarbonyl group for protection and mixed acid anhydride for coupling Multigram amounts of glycyl-L-histidyl by conventional solution phase methods using physical methods. ru-shi-lysyl-shi-prolyl-1,-valyl-L-phenylalanyl-shiba synthesized phosphorus.
簡単に言えば、Ｌ−バリンベンジルエステルｐ−スルホン酸塩を、がクプリング 剤としてイソブチルクロロホルメート及びトメチルモルホリンを使用してｔ−ブ チルオキシカルボニル−し−フェニルアラニンとカップリングした（−２０℃で ２時間、次いで周囲温度で１時間）。次いでジペプチドのｔ−ブチルオキシカル ボニル保護基をジクロロメタン中３０％のトリフルオロ酢酸により室温で３０分 間で除去した。所望のペプチドを得るため、ブロックされたアミノ酸（ｔ−ブチ ルオキシカルボニル−し−バリン、ｔ−プチルオキシカルボニルーし一プロリン 、Ｎ” −ｔ−ブチルオキシカルボニル−Ｎ＠−ベンジルオキシカルボニル−し −リシン、Ｎ”−ｔ−ブチルオキシカルボニル−Ｎ１ｍ−ベンジルオキシカルボ ニル−Ｌ−ヒスチジン、ベンジルオキシカルボニルグリシン）を添加し、ｔ−ブ チルオキシカルボニル保護基を逐次除去した。ｌＯ％Ｐｄ−Ｃ触媒の存在下で５ 日間にわたって酢酸中で水素を使用して最終ペプチドを完全に脱保護した。最終 ペプチドを水から凍結乾燥し、Ｃ−１８逆相カラムによる液体クロマトグラフィ ーにより精製して所望のへキサペプチドをマルチグラム量で生成した。Briefly, L-valine benzyl ester p-sulfonate is t-butyl chloroformate and tomethylmorpholine as agents. Coupled with tyloxycarbonyl-phenylalanine (at -20°C) 2 hours then 1 hour at ambient temperature). Then the t-butyloxycarboxylic acid of the dipeptide Bonyl protecting group was removed with 30% trifluoroacetic acid in dichloromethane for 30 min at room temperature. removed in between. To obtain the desired peptide, blocked amino acids (t-butyl t-butyloxycarbonyl-thi-valine, t-butyloxycarbonyl-thi-proline , N''-t-butyloxycarbonyl-N@-benzyloxycarbonyl- -lysine, N''-t-butyloxycarbonyl-N1m-benzyloxycarbo t-butyl-L-histidine, benzyloxycarbonylglycine). The thyloxycarbonyl protecting group was removed sequentially. 5 in the presence of lO% Pd-C catalyst The final peptide was completely deprotected using hydrogen in acetic acid over a period of days. Final Peptides were lyophilized from water and subjected to liquid chromatography on a C-18 reverse phase column. to produce multigram quantities of the desired hexapeptide.
得られるヘプタペプチドグリシル−し−ヒスチジルルーリシル−し−プロリル− Ｌ−バリル−Ｌ−フェニルアラニル−Ｌ−バリンを、水に溶解し、等モル量の酢 酸第二銅と混合することにより銅（ＩＩ）錯体に変換した。ｐＨを水酸化ナトリ ウムで中性まで上げた。その溶液を３℃で２０．０００Ｘｇで１時間遠心分離し て難溶性物質を除去した。The resulting heptapeptide glycyl-histidyl-prolyl- Dissolve L-valyl-L-phenylalanyl-L-valine in water and add an equimolar amount of vinegar. It was converted to a copper(II) complex by mixing with cupric acid. Sodium hydroxide pH I raised it to neutral with um. The solution was centrifuged at 20,000×g for 1 hour at 3°C. The poorly soluble substances were removed.
上澄み液を凍結乾燥してグリシル−１，−ヒスチジル−し−リシル−し−プロリ ル−１−／＜リルーし一フェニルアラニルーし一バリン：銅（ＩＩ）を得た。The supernatant was lyophilized to give glycyl-1,-histidyl-lysyl-prolyl. Ru-1-/<Re-ru, one-phenylalanyl-one, one-valine: copper(II) was obtained.
上記の系統的な合成は、最小の精製でもって高純度のマルチグラム量の所望のペ プチドを得る点で幾つかの固相法よりも有利であることがわかった。The systematic synthesis described above yields highly pure multigram amounts of the desired compound with minimal purification. It was found to be advantageous over some solid phase methods in obtaining peptides.
実施例５ ルポニルーし一リジンの溶液を−１５℃でＮ−メチルモルホリン、イソブチルク ロロホルメート、及びオクチルアミンで処理した。次いで、得られた完全保護の オクチルアミドを室温で１／２のトリフルオロ酢酸／ジクロロメタンで処理し、 飽和重炭ジカルボニル−し一ヒスチジン、Ｎ−メチルモルホリン、及びイソブチ ルクロロホルメートから乾燥テトラヒドロフラン中で一１５℃で調製した溶液に 添加した。Example 5 A solution of luponyl-lysine and N-methylmorpholine and isobutyl lysine was prepared at -15°C. Treated with loloformate and octylamine. Then, the resulting full protection Octylamide was treated with 1/2 trifluoroacetic acid/dichloromethane at room temperature, Saturated heavy carbon dicarbonyl monohistidine, N-methylmorpholine, and isobutylene to a solution prepared at -15 °C in dry tetrahydrofuran from chlorchloroformate. Added.
先に生成した完全に保護されたジペプチドを室温で１／２のトリフルオロ酢酸／ ジクロロメタンで処理し、続いて飽和重炭酸カリウム水溶液で中和した。酢酸エ チルで抽出し、蒸発させて部分的に脱ブロックしたジペプチドを得、これを−１ ５℃で乾燥テトラヒドロフラン中でＮｏ−ベンジルオキシカルボニルグリシン、 Ｎ−メチルモルホリン、及びイソブチルクロロホルメートから調製した溶液に添 加した。得られた保護されたトリペプチドを氷酢酸中で１０％のパラジウム／カ ーボンの存在下で水素による処理により脱ブロックした。濾過し、凍結乾燥して 標題化合物をその三酢酸塩として得た。The previously generated fully protected dipeptide was diluted with 1/2 trifluoroacetic acid/ Treatment with dichloromethane followed by neutralization with saturated aqueous potassium bicarbonate. acetic acid Extraction with chill and evaporation yielded a partially deblocked dipeptide, which was No-benzyloxycarbonylglycine in dry tetrahydrofuran at 5°C, Added to a solution prepared from N-methylmorpholine and isobutyl chloroformate. added. The resulting protected tripeptide was dissolved in 10% palladium/carbon in glacial acetic acid. Deblocking was achieved by treatment with hydrogen in the presence of carbon. filtered and freeze dried The title compound was obtained as its triacetate salt.
ンをテトラヒドロフラン（ＴＨＦ）に溶解し、１当量のＮ−メチルモルホリンで 中和した。次いでそれを、イソブチルクロロホルメート及びトメチルモルホリン を使用してベンジルグリシネートｐ−トルエンスルホン酸塩とカップリングした 。−２０’Ｃで２時間、周囲温度で更に１時間後に、その反応を２Ｎの重炭酸カ リウム水溶液で停止した。その生成物を酢酸エチルで抽出し、最初にＩＭのクエ ン酸水溶液で洗浄し、次に飽和重炭酸ナトリウム液で洗浄した。有機相を無水硫 酸ナトリウムで乾ンンルオキシカルボニルーし一ヒスチジルーグリシネートを得 た。was dissolved in tetrahydrofuran (THF) and treated with 1 equivalent of N-methylmorpholine. Neutralized. It was then combined with isobutyl chloroformate and tomethylmorpholine. coupled with benzylglycinate p-toluenesulfonate using . After 2 hours at -20'C and an additional hour at ambient temperature, the reaction was quenched with 2N bicarbonate. It was stopped with aqueous solution of lium. The product was extracted with ethyl acetate and first quenched with IM. The solution was washed with aqueous acid solution and then with saturated sodium bicarbonate solution. Organic phase with anhydrous sulfur Dried with sodium hydroxide to give histidylglycinate. Ta.
この生成物を無水のメタノール性塩化水素（０℃で飽和）に５分間で溶解し、続 いて減圧下で溶媒を除去し、ベンジ／ｌ／Ｎ”″−ベンジルオキシカルボニルー し一ヒスチジルーグリシネートを生成した。これをテトラヒドロフランに溶解し 、イソシル−Ｌ−ヒスチジル−グリシネートを生成した（−２０℃で３時間、次 いで周囲温度で１時間）。次いでこの生成物をメタノール／酢酸［１：ｌ（ｖ／ ｖ）］に溶解し、１０％のＰｄ−Ｃ触媒の存在下で一夜にわたって水素化した。This product was dissolved in anhydrous methanolic hydrogen chloride (saturated at 0°C) for 5 minutes and then The solvent was removed under reduced pressure and the benzyl/l/N""-benzyloxycarbonyl Then, histidyl glycinate was produced. Dissolve this in tetrahydrofuran , produced isosyl-L-histidyl-glycinate (3 hours at -20°C, then for 1 hour at ambient temperature). This product was then dissolved in methanol/acetic acid [1:l (v/ v)] and hydrogenated overnight in the presence of 10% Pd-C catalyst.
得られたし一リシルーし一ヒスチジルーグリシンを水から数回凍結乾燥し、次い でＣ−１８逆相カラムによる液体クロマトグラフィーにより精製して所望のトリ ペプチド三酢酸塩を泡状の白色の固体ンをテトラヒドロフラン（ＴＨＦ）に溶解 し、１当量のＮ−メチルモルホリンで中和した。次いでそれを、イソブチルクロ ロホルメート及びトメチルモルホリンを使用してグリシンアミド塩酸塩とカップ リングさせた。−２０℃で２時間、ついで室温で更に１時間後に、その反応を２ Ｎの重炭酸カリウム水溶液で停止した。その生成物を酢酸エチルで抽出し、最初 にＩＭのクエン酸水溶液で洗浄し、次に飽和重炭酸ナトリウム液で洗浄した。有 機相を無水硫酸ナトリウムで乾燥させた。The obtained histidyl-glycine was lyophilized several times from water and then The desired trifluoride was purified by liquid chromatography using a C-18 reverse phase column. Dissolve the peptide triacetate as a foamy white solid in tetrahydrofuran (THF). and neutralized with 1 equivalent of N-methylmorpholine. It was then converted into isobutylchloride. cup with glycinamide hydrochloride using roformate and tomethylmorpholine I made a ring. After 2 hours at -20°C and another 1 hour at room temperature, the reaction was carried out for 2 hours. Quenched with aqueous potassium bicarbonate solution. The product was extracted with ethyl acetate and first Washed with IM aqueous citric acid solution and then with saturated sodium bicarbonate solution. Yes The organic phase was dried over anhydrous sodium sulfate.
ルーＬ−ヒスチジルーグリシンアミドを得た。Ru-L-histidyl-glycinamide was obtained.
その生成物を無水のメタノール性塩化水素（０℃で飽和）に３０分間で溶解し、 続いて減圧下で溶媒を除去し、ベンジルＮ Ｉｓ＋−ベンジルオキシカルボニル −し−ヒスチジル−グリシンアミドを生成した。これをテトラヒドロフランに溶 解し、イルボニル−Ｉ、−リシル−Ｌ−ヒスチジル−グリシンアミドを添加した （−２０℃で３時間、次いで周囲温度で１時間）。次いでこの生成物を氷酢酸に 溶解し、１０％のＰｄ−Ｃ触媒の存在下で一夜にわたって水素化した。得られた し一すシルーＬ−ヒスチジルーグリシンアミドを水から数回凍結乾燥し、次いｒ −Ｃ−１８逆相カラムによる液体クロマトグラフィーにより精製して所望のトリ ペプチドアミドを三酢酸塩として得た。The product was dissolved in anhydrous methanolic hydrogen chloride (saturated at 0°C) for 30 minutes, Subsequently, the solvent was removed under reduced pressure, and benzyl N Is+-benzyloxycarbonyl -histidyl-glycinamide was produced. Dissolve this in tetrahydrofuran. and added irbonyl-I,-lysyl-L-histidyl-glycinamide. (3 hours at -20°C then 1 hour at ambient temperature). This product is then dissolved in glacial acetic acid. Dissolved and hydrogenated in the presence of 10% Pd-C catalyst overnight. obtained Shiichisu Silu L-Histidyl Glycinamide was lyophilized several times from water and then Purification by liquid chromatography using a -C-18 reverse phase column to obtain the desired triglyceride. The peptide amide was obtained as the triacetate salt.
グリシン、オクチルアルコール、ｐ−トルエンスルホン酸−水和物、及びベンゼ ンを、ディージ・スタークトラップを使用して２４時間の期間にわたって一緒に 還流させて発生した水を共沸により除去した。室温に冷却し、次いで乾燥エチル エーテルを添加した後、オクチルグリシネートｐ−トルエンスルホン酸塩を吸引 濾過により回収した。その塩を飽和重炭酸ナトリウム液で処理し、ジクロロメタ ンで抽出した。蒸発させて遊離アミンを得、これを乾燥テトラヒドロフラン（Ｔ ＨＦ）にルオキシ力ルポニルーＬ−ヒスチジン、Ｎ−メチルモルホリン、及びイ ソブチルクロロホルメートの攪拌溶液に添加した。−２０℃で２時間、ついで室 温で更に１時間後に、その反応を２Ｎの重炭酸カリウム水溶液で停止した。その 生成物を酢酸エチルで抽出し、ＩＭのクエン酸水溶液で洗浄し、次に飽和重炭酸 ナトリウム液で洗浄した。有機相を無水硫酸ナトリウムで乾燥させ、濾過し、蒸 発させた。Glycine, octyl alcohol, p-toluenesulfonic acid-hydrate, and benzene together over a period of 24 hours using the Digi Stark Trap. The water generated during reflux was removed azeotropically. Cool to room temperature, then dry ethyl After adding the ether, aspirate the octylglycinate p-toluenesulfonate. Collected by filtration. The salt was treated with saturated sodium bicarbonate solution and dichloromethane was added. Extracted with Evaporation gave the free amine, which was dissolved in dry tetrahydrofuran (T HF), luponyl-L-histidine, N-methylmorpholine, and Added to a stirred solution of sobutyl chloroformate. -20℃ for 2 hours, then room temperature After an additional hour at room temperature, the reaction was quenched with 2N aqueous potassium bicarbonate. the The product was extracted with ethyl acetate, washed with IM aqueous citric acid, then saturated bicarbonate. Washed with sodium solution. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. I let it emanate.
得られた完全に保護されたジペプチドエステルをジクロロメタン中３０％のトリ フルオロ酢酸で周囲温度で４０分間処理し、飽和重炭酸ナトリウム水溶液で中和 し、酢酸エチルで抽出した。The resulting fully protected dipeptide ester was dissolved in 30% trichloride in dichloromethane. Treat with fluoroacetic acid for 40 min at ambient temperature and neutralize with saturated aqueous sodium bicarbonate solution. and extracted with ethyl acetate.
蒸発させて部分的に脱保護されたジペプチドを得、これを乾燥叱に再度溶解チル モルホリン及びイソブチルクロロホルメートの攪拌溶液に添加した。生成した完 全に保護されたトリペプチドエステルを氷酢酸中で周囲温度で１０％のＰｄ−Ｃ 触媒の存在下で水素ガスによる処理により完全に脱保護した。セライトの層によ り濾過し、水から凍結乾燥し、Ｃ−１８逆相カラムによる液体クロマトグラフィ ーにより精製して所望のトリペプチドエステルをその三酢酸塩として得た。Evaporate to obtain a partially deprotected dipeptide, which is redissolved in a dry solution and chilled. Added to a stirred solution of morpholine and isobutyl chloroformate. The generated complete The fully protected tripeptide ester was dissolved in 10% Pd-C in glacial acetic acid at ambient temperature. Complete deprotection was achieved by treatment with hydrogen gas in the presence of a catalyst. Due to the celite layer lyophilized from water and subjected to liquid chromatography on a C-18 reverse phase column. The desired tripeptide ester was obtained as its triacetate salt.
α窒素のためのｔ−ブチルオキシカルボニル保護基、側鎖保護のためのベンジル オキシカルボニル基及びカップリングのための混合酸無水物法を使用する通常の 溶液相法によりマルチグラム量のし一すシルーＬ−ヒスチジル−グリシルルーバ リル−し−フェニルアラニル−Ｌ−バリンを合成した。簡単に言えば、Ｌ−バリ ンベンジルエステルｐ−トルエンスルホン酸塩を、カップリング剤としてイソブ チルクロロホルメート及びトメチルモルホリンを使用してｔ−ブチルオキシカル ボニル−し−フェニルアラニンとカップリングした（−２０℃で２時間、次いで 周囲温度で１時間）。t-butyloxycarbonyl protecting group for alpha nitrogen, benzyl for side chain protection Conventional using oxycarbonyl group and mixed anhydride method for coupling Silu L-histidyl-glycyl Ruba in multigram quantities by solution phase method Lyle-shi-phenylalanyl-L-valine was synthesized. Simply put, L-Bali benzyl ester p-toluenesulfonate as a coupling agent. t-Butyloxycarboxylic acid using methyl chloroformate and tomethylmorpholine Coupled with Bonyl-di-phenylalanine (2 hours at -20°C, then 1 hour at ambient temperature).
次いでジペプチドのｔ−ブチルオキシカルボニル保護基をジクロロメタン中３０ ％のトリフルオロ酢酸により室温で３０分間で除去した。所望のペプチドを得る ため、ブロックされたアミノ酸（ｔ−ブチルオキシカルボニル−Ｌ−バリン、ｔ −ブチルオを逐次添加した。氷酢酸中で５日間にわたって１０％のＰｄ−Ｃ触媒 の存在下で水素ガスを使用して最終ペプチドを完全に脱保護した。最終ペプチド を水から凍結乾燥し、Ｃ−１８逆相カラムによる液体クロマトグラフィーにより 精製して所望のへキサペプチドをマルチグラム量で生成した。The dipeptide's t-butyloxycarbonyl protecting group was then removed in dichloromethane for 30 minutes. % trifluoroacetic acid for 30 minutes at room temperature. Obtain the desired peptide Therefore, blocked amino acids (t-butyloxycarbonyl-L-valine, t- - Butyruo was added sequentially. 10% Pd-C catalyst over 5 days in glacial acetic acid The final peptide was completely deprotected using hydrogen gas in the presence of . final peptide was lyophilized from water and subjected to liquid chromatography on a C-18 reverse phase column. Purification produced multigram quantities of the desired hexapeptide.
上記の系統的な合成は、最小の精製でもって高純度のマルチグラム量の所望の生 成物を与える点で幾つかの固相法よりも有利であることがわかった。The systematic synthesis described above yields highly pure multigram quantities of the desired product with minimal purification. It has been found to be advantageous over some solid phase methods in providing the desired product.
溢血動物の毛髪成長の刺激を実証するために、１５目にマウスの背中を電気カミ ソリで剃った。水溶液中の次第に増加する投薬量のグリシル−し−ヒスチジル− Ｌ−リシル−し−バリル−Ｌ−フェニルアラニル−Ｌ−バリンニ鋼（ＩＩ）を三 箇所で皮膚の下に浸透させた。マウスを剃った領域及び注射部位の毛髪成長の徴 候に関して毎日調べた。グリシ・ル−Ｌ−ヒスチジル−し一すシル−し一バリル −Ｌ−フェニルアラニル−した。このような促進された毛髪成長は、剃った領域 の毛髪の通常の再成長を越えている。両方の注射部位の毛髪成長は陽性の応答と 考えられる。To demonstrate the stimulation of hair growth in bleeding animals, the backs of mice were electrically shaved on the 15th day. I shaved with a sled. Increasing dosages of glycyl-histidyl in aqueous solution L-lysyl-valyl-L-phenylalanyl-L-valinium steel (II) It was penetrated under the skin in spots. Signs of hair growth in the shaved area of the mouse and the injection site I researched the weather every day. Glycy-L-Histidyl-Shi-Syl-Shi-Valyl -L-phenylalanyl-. Such accelerated hair growth is achieved in shaved areas is beyond the normal regrowth of hair. Hair growth at both injection sites indicates a positive response Conceivable.
→の実験を表１に要約する。食塩水を注射したマウスで応答がなかったことに較 べて、陽性の応答がグリシル−し−ヒスチジル−し−リシル−し−バリル−Ｌ− フェニルアラニル−Ｌ−バリン：銅（ＩＩ）で注射したマウスの８０〜９０％で 観察された。→The experiments are summarized in Table 1. compared to no response in mice injected with saline. In all cases, a positive response was glycyl-histidyl-lysyl-valyl-L Phenylalanyl-L-valine: in 80-90% of mice injected with copper(II) observed.
０、１０ ８６（ｎ＝７） ０、２５ ８９（ｎ＝９ ） ０、５０ ８９（ｎ＝５４ ） １、００ ９５（ｎ＝２０ ） 食塩水 （１（ｎ＞５０） グリシル−し−ヒスチジル−し−リシル−し−バリル−Ｌ−フェニルアラニル− Ｌ〜バリン−銅（Ｈ）の注射後に、毛髪成長の指示が１０日以内に見られた。最 初の目視の徴候は、注射部位の周囲の円形の領域中の皮膚の暗化である。この領 域のサイズは一般に投薬量依存性であり、投薬量の増加と共に増加する。０．５ ■の注射は通常直径約０．５ｃｍの円形の成長を生じる。活性な毛髪成長は１４ 〜２０日の間に起こり、最高の効果が２８日までに見られる。0, 10 86 (n=7) 0, 25 89 (n=9) 0, 50 89 (n=54) 1,0095 (n=20) Salt solution (1 (n>50) glycyl-histidyl-lysyl-valyl-L-phenylalanyl- After injection of L~valine-copper (H), indications of hair growth were seen within 10 days. most The first visual sign is darkening of the skin in a circular area around the injection site. this territory The size of the zone is generally dose dependent and increases with increasing dosage. 0.5 Injection (2) usually produces a circular growth about 0.5 cm in diameter. Active hair growth is 14 Occurs between ~20 days, with best effects seen by day 28.
図２は二つの注入部位に於ける促進された毛髪成長及び周囲の剃られた領域に於 ける毛髪成長の欠如を示すグリシル−し−ヒスチジル−し−リシル−し−バリル −Ｌ−フェニルアラニル−Ｌ−バリン：銅（１１）溶液で注射されたマウスの写 真である。図３は注入の日から２５日目の食塩水で一箇所で注射された対照マウ ス（左側のマウス）及び促進された毛髪成長を示すグリシル−し−ヒスチジル− し−リシル−Ｌ−バリル−Ｌ−フェニルアラニル−Ｌ−バリン：銅（１１）溶液 で一箇所で注射されたマウス（右側のマウス）の写真である。Figure 2 shows the stimulated hair growth at the two injection sites and the surrounding shaved area. Glycyl-histidyl-lysyl-lysyl-valyl indicative of lack of hair growth -L-Phenylalanyl-L-valine: Photograph of a mouse injected with copper(11) solution True. Figure 3 shows control mice injected at one location with saline 25 days after the day of injection. (mouse on the left) and glycyl-histidyl-glycyl-histidyl- showing accelerated hair growth. Shi-lysyl-L-valyl-L-phenylalanyl-L-valine: copper (11) solution This is a photograph of a mouse (mouse on the right) that was injected at a single location.
注射の部位から採取された皮膚生体組織検査の組織部分は発育期状態の小胞を明 らかにする。皮膚生体組織を促進された毛髪成長の領域から採取し、パラフィン 中に埋め込み、切断し、組織評価のために染色した。得られるスライドの顕微鏡 検査は、小胞が皮下脂肪層中に深（延びていることを明らかにした。更に、周囲 の皮膚は皮膚層中にある休止期状態の小胞を含み、注射部位に近づくにつれて効 果の勾配が観察される。また、注射部位に近づ（程、小胞突起が深くなり、脂肪 層が厚くなる。図４はグリシル−し−ヒスチジル−し−リシル−し−バリル−Ｌ −フェニルアラニル−Ｌ−バリン：銅（ＩＩ）で注射されたマウスからの組織部 分を示す写真である。注射の領域は写真の右側にある。上奏密度及び皮下脂肪層 の減少が、注射部位からの距離が次第に増すにつれて観察される。Tissue from a skin biopsy taken from the injection site reveals vesicles in their nascent state. Make it clear. Skin tissue was collected from areas of stimulated hair growth and paraffinized. were embedded, sectioned, and stained for histological evaluation. Microscope of resulting slides Examination revealed that the vesicles extended deep into the subcutaneous fat layer. The skin of the skin contains quiescent vesicles located in the skin layers, which become more effective as the injection site is approached. A gradient of fruits is observed. In addition, the closer you get to the injection site, the deeper the vesicle protrusion becomes and the fat The layer becomes thicker. Figure 4 shows glycyl-shi-histidyl-shi-lysyl-shi-valyl-L. - Phenylalanyl-L-valine: tissue section from mice injected with copper(II) This is a photo showing the minutes. The area of injection is on the right side of the photo. Epidermal density and subcutaneous fat layer A decrease in is observed with increasing distance from the injection site.
実施例１１ グリシル−し−ヒスチジル−し−リシンオクチルエステル・金属イオン（ＩＩ） 錯体の皮下注射によるマウスの毛髪成長の刺激マウスを剃髪し、ペプチド対金属 の比２：ｌのグリシル−し−ヒスチジル−し−リシンオクチルエステル：金属イ オン（Ｇｌ（Ｌオクチル・金属イオン）の水溶液で三箇所で注射した。マウスに 対し５００μｇの投薬量を注射した。Example 11 Glycyl-histidyl-lysine octyl ester/metal ion (II) Stimulation of hair growth in mice by subcutaneous injection of the complex peptide versus metal by shaving the mouse. The ratio of 2:l glycyl-histidyl-lysine octyl ester:metallic acid Injected with an aqueous solution of Gl (L octyl metal ion) at three locations. A dose of 500 μg was injected.
両方の注射部位に於ける毛髪成長は陽性応答と考えられる。実験の結果を表２に 要約する。注射後２〜３週間以内に毛髪成長のかなりの促進があった。食塩水を 注射したマウスは毛髪成長の促進を示さなかった。Hair growth at both injection sites is considered a positive response. The results of the experiment are shown in Table 2. Summarize. There was significant stimulation of hair growth within 2-3 weeks after injection. salt water Injected mice showed no stimulation of hair growth.
（陽性数７合計数） Ｇ）ｔＬオクチル：Ｃｕ（ＴＩ） ４／４ＧＨＬオクチル：Ｃｄ（Ｈ） ２／４ ＧＨＬオクチル：Ｃｏ（ＩＩ） ４／４Ｇ）ｌＬオクチル： ５ｎ（ＩＩ） ２ ／４ＧＨＬオクチル： Ｆｅ（ＩＩ ） ２／４ＧＨＩ、オクチル：Ｍｇ（ＩＩ ） ２／４実施例１２ Ｌ−リシルルーヒスチジル−グリシンオクチルエステル：銅（ＩＩ）及びレリシ ルーＩ、−ヒスチジル−グリシル−し−バリル−Ｌ−フェニルアラニル−Ｌ−バ リン：銅（ＩＩ）の皮下注射によるマウスの毛髪成長の刺激マウスを剃髪し、ペ プチド対金属の比２．Ｉで、マウスに対し５００μｇ及びｌ０００μｇの投薬量 でし一リシルーし一ヒスチジルーグリシンオクチルエステル：銅（ＩＩ）（ＬＨ Ｇオクチル・Ｃｕ）及びレリシルーＬ〜ヒスチジル−グリシル−し−バリル−Ｌ −フェニルアラニル−Ｌ−バリン：銅（ＩＩ ）（ＬＧ）ｒｖＦＶ：Ｃｕ）の水 溶液で三箇所で注射した。両方の注射部位に於ける毛髪成長は陽性応答と考えら れる。注射後２〜３週間以内に毛髪成長のかなりの促進があった。食塩水を注射 したマウスは促進を示さなかった。この実験の結果を表３に要約する。(7 total number of positives) G) tL octyl: Cu (TI) 4/4 GHL octyl: Cd (H) 2/4 GHL octyl: Co(II) 4/4G)lL octyl: 5n(II) 2 /4GHL Octyl: Fe(II) 2/4GHI, Octyl: Mg(II ) 2/4 Example 12 L-lysyl-histidyl-glycine octyl ester: copper(II) and relicyl RuI, -Histidyl-glycyl-S-valyl-L-phenylalanyl-L-ba Phosphorus: Stimulation of hair growth in mice by subcutaneous injection of copper(II) Mice were shaved and Peptide to metal ratio2. I at doses of 500 μg and 1000 μg for mice. Histidyl-glycine octyl ester: Copper(II) (LH G octyl Cu) and relicyl L ~ histidyl-glycyl-shi-valyl-L -Phenylalanyl-L-valine: Copper (II) (LG) rvFV: Cu) water Three injections were made with the solution. Hair growth at both injection sites is considered a positive response. It will be done. There was significant stimulation of hair growth within 2-3 weeks after injection. injection of saline mice showed no facilitation. The results of this experiment are summarized in Table 3.
青１ 化合物 投薬量 陽性応答 （陽性数７合計数） ＬＮＧオクチル：Ｃｕ ０１５ｍｇ ８／８ １００％１０■ ５１５ １００ ％ ＬＨＧＶＦＶ：Ｃｕ ０．５ｍｇ ９／１０ ９０％１．０■ ５１５ １００ ％ 実施例１３ グリシル−Ｌ−ヒスチジル−し−リシル−バリル−フェニルアラニル−バリン： 銅（ＩＩ）の局所適用によるマウスの毛髪成長の刺激本発明のペプチド−金属イ オン組成物を含む製薬組成物の局所適用後の毛髪成長を実証するために、マウス を剃髪し、ペプチド対金属の比２：１のグリシル−し−ヒスチジル−し−リシル −Ｌ−バリル−Ｌ−フェニルアラニル−し−バリン：銅（ＩＩ）（Ｇ）ＬＶＦＶ ： Ｃｕ ）を含む下記の製薬組成物で毎旧治療した。blue 1 Compound Dosage Positive Response (7 total number of positives) LNG octyl: Cu 015mg 8/8 100% 10 ■ 515 100 % LHGVFV: Cu 0.5mg 9/10 90% 1.0 ■ 515 100 % Example 13 Glycyl-L-histidyl-lysyl-valyl-phenylalanyl-valine: Stimulation of hair growth in mice by topical application of copper(II) To demonstrate hair growth after topical application of pharmaceutical compositions, including compositions on mice. was shaved and treated with glycyl-cys-histidyl-cys-lysyl at a peptide to metal ratio of 2:1. -L-valyl-L-phenylalanyl-shi-valine: copper (II) (G) LVFV The patient was previously treated with the following pharmaceutical composition containing Cu: Cu.
ＧＨＬＶＦＶ ： Ｃｕ １％（ｗ／ｗ）ノンオキシノ−ルー９ ５％ ユニベースクリーム ９４％ 治療部位の毛髪成長は陽性応答と考えられる。局所組成物で治療した５匹のマウ スのうちの４匹（８０％）が局所適用の領域で促進された毛髪成長を示した。GHLVFV: Cu 1% (w/w) Non-oxyno-ru 9 5% Unibase Cream 94% Hair growth in the treated area is considered a positive response. Five mice treated with topical composition Four of the animals (80%) showed enhanced hair growth in the area of topical application.
実施例１４ グリシル−し−（３−メチル）−ヒスチジル−し−リシル−グリシル−Ｌ−トリ プトファン：銅（ＩＩ）の皮下注射によるマウスの毛髪成長の刺激マウスを剃髪 し、種々の投薬量のグリシル−し−（３−メチル）−ヒスチジル−Ｌ〜リシル− グリシル−Ｌ−トリプトファン：銅（ＩＩ）で三箇所で皮肉注射した。注射後２ 〜３週間以内に毛髪成長がマウスに観察された。両方の注射部位の毛髪成長は陽 性応答と考えられる。結果を表４に示す。Example 14 Glycyl-(3-methyl)-histidyl-lysyl-glycyl-L-tri Ptophan: stimulation of hair growth in mice by subcutaneous injection of copper(II) shaved mice and various dosages of glycyl-(3-methyl)-histidyl-L-lysyl- Glycyl-L-tryptophan: Cycnic injections were made at three sites with copper(II). After injection 2 Hair growth was observed in mice within ~3 weeks. Hair growth at both injection sites is positive. It is thought to be a sexual response. The results are shown in Table 4.
実験１５００■ ５１５ １００％ 実験２２５０■ ５１５ １００％ 実施例１５ マウスの毛髪成長を刺激するためのグリシル−し−ヒスチジル−し−リシンｎ− オクチルエステル：銅（ＴＩ）の使用 マウスを剃髪し、マウスに対し５００μｇの投薬量でグリシル−し−ヒスチジル −し−リシンｎ−オクチルエステル：銅（ＩＩ）を１回注射した。図５は、５０ ０μｇの注射後２〜３週間以内に毛髪成長のかなりの促進があったことを示す。Experiment 1500 ■ 515 100% Experiment 2250 ■ 515 100% Example 15 Glycyl-histidyl-lysine n- for stimulating hair growth in mice Octyl ester: Use of copper (TI) Mice were shaved and mice were treated with glycyl-histidyl at a dose of 500 μg. -Rysine n-octyl ester: one injection of copper(II). Figure 5 shows 50 It shows that there was a significant promotion of hair growth within 2-3 weeks after injection of 0 μg.
食塩水を注射したマウスは促進を示さなかった。Mice injected with saline showed no facilitation.
促進された毛髪成長の領域で、皮下脂肪層の厚さのかなりの増加があった。この 脂肪層の厚さは毛髪成長と直接関連することが知られている。皮下脂肪のこの増 加は、２１日目に生体組織検査試料をその領域から採取し、組織スライドのため に切断することにより示される。図６は脂肪層のこの増加を示す。注射領域は右 側にあり、隣接する未注射領域が写真の左側にある。脂肪細胞の数及びサイズの 両方で明らかな増加があった。測定は、注射部位付近の皮膚中で皮下脂肪層の約 ３倍の増加があることを示す。In the areas of stimulated hair growth, there was a significant increase in the thickness of the subcutaneous fat layer. this It is known that the thickness of the fat layer is directly related to hair growth. This increase in subcutaneous fat A biopsy sample was taken from the area on day 21 and used for histological slides. This is shown by cutting to . Figure 6 shows this increase in fat layer. Injection area is on the right side, with the adjacent uninjected area on the left side of the photo. number and size of fat cells There was a clear increase in both. Measurements are taken at approximately the subcutaneous fat layer in the skin near the injection site. It shows that there is a 3-fold increase.
実施例１６ マウスの毛髪成長を刺激するためのグリシル−し−ヒスチジルルーリシンデシル エステル銅：（ＴＩ）の使用 １０匹の群のマウスを剃髪し、マウスに対し５００μｇの投薬量でグリシル−し −ヒスチジル−Ｌ−リシンデシルエステル：銅（４４）を１回注射した。図７は 、注射後２〜３週間以内に毛髪成長のかなりの促進があったことを示す。また、 顕微鏡検査は増大された毛髪成長、脂肪細胞層及び注射部位の周囲の領域中の増 加された上音密度の証拠を与えた。図８は、促進された成長の領域の皮下脂肪内 に現れる毛幹単位の著しい増殖があることを示す。注射部位から遠い位置にある 皮膚の検査は通常の組織を示した。Example 16 Glycyl-histidylluricindecyl for stimulating hair growth in mice Use of ester copper: (TI) Groups of 10 mice were shaved and mice were glycyl-treated at a dose of 500 μg. - Histidyl-L-lysine decyl ester: one injection of copper (44). Figure 7 is , indicating that there was significant promotion of hair growth within 2-3 weeks after injection. Also, Microscopic examination shows increased hair growth, fat cell layer and increase in the area surrounding the injection site. gave evidence of added overtone density. Figure 8 shows subcutaneous fat in areas of accelerated growth. This indicates that there is significant proliferation of hair shaft units appearing in the . located far from the injection site Skin examination showed normal histology.
実施例Ｉ７ マウスの毛髪成長を刺激するためのグリシル−し−ヒスチジル−し−リシンパル ミチルエステル：銅（ＩＩ）の使用 １０匹の群のマウスを剃髪し、マウスに対し５００μｇの投薬量でグリシル−し −ヒスチジル−Ｌ−リシンバルミチルエステル：銅（ＩＩ）を１回注射した。注 射後２〜３週間以内に毛髪成長のかなりの促進があった。促進された毛髪成長の 領域中の組織部分は上記のものと同様であった。これが図９に示される。顕微鏡 写真は、グリシル−し−ヒスチジル−し−リシンデシルエステルニ銅（１１）注 射後に見られたものと同様の皮下脂肪層内の多数の発達している上置（図９Ｂ） を示し、一方、未治療領域中の組織部分の顕微鏡写真（図９Ａ）はこのような上 置発達を明らかにしない。Example I7 Glycyl-Histidyl-Lysympal for Stimulating Hair Growth in Mice Use of methyl ester: copper(II) Groups of 10 mice were shaved and mice were glycyl-treated at a dose of 500 μg. - Histidyl-L-lysine balmityl ester: one injection of copper(II). note There was significant stimulation of hair growth within 2-3 weeks after injection. accelerated hair growth The histology in the area was similar to that described above. This is shown in FIG. microscope The photo shows dicopper glycyl-histidyl-lysine decyl ester (11) Note Numerous well-developed epiphytes within the subcutaneous fat layer similar to those seen after injection (Figure 9B) , whereas the micrograph of the tissue section in the untreated area (Fig. 9A) shows such an upper Does not reveal positional development.
ＦＩＧ。６ ｒ 】 ＦＩＧ。９Ａ ＦＩＧ。９Ｂ 国際調査報告 、、、、、、−、、、−、＋、、、−、−ｐＣＴ／ｌｌ５Ｑｎ／ｎｉｌ、ＱＲ国 際調査報告 ＰＣＴ／ＵＳ ９０１０６５９８ Ｓ＾ ４２４１５FIG. 6 r ] FIG. 9A FIG. 9B international search report , , , , , -, , -, +, , -, -pCT/ll5Qn/nil, QR country international investigation report PCT/US 90106598 S^ 42415
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| US07/436,382 US5120831A (en) | 1985-02-08 | 1989-11-13 | Metal-peptide compositions |
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| WO1995023580A1 (en) * | 1994-03-03 | 1995-09-08 | Procyte Corporation | Preventive and remedy for secondary depilation |
| JP2006504448A (en) * | 2002-07-02 | 2006-02-09 | プロサイト コーポレイション | Composition containing peptide copper complex and soft tissue filler |
| JP2013010769A (en) * | 2003-07-18 | 2013-01-17 | Inst Europeen De Biologie Cellulair | Use of peptide conjugate for preparing composition for alopecia preventive and curative treatment |
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| US5728714A (en) * | 1985-07-18 | 1998-03-17 | Proctor; Peter H. | Method for treating hair loss using tempo |
| US5714482A (en) * | 1985-07-18 | 1998-02-03 | Proctor; Peter H. | Topical spin labels and method |
| US6150405A (en) * | 1985-07-18 | 2000-11-21 | Proctor; Peter H. | Hair loss treatment with ascorbates |
| US5723502A (en) * | 1985-07-18 | 1998-03-03 | Proctor; Peter H. | Topical spin trap composition and method |
| US5714510A (en) * | 1985-07-18 | 1998-02-03 | Proctor; Peter H. | Topical proxyl composition and method |
| US5470876A (en) * | 1985-07-18 | 1995-11-28 | Proctor; Peter H. | Topical sod for treating hair loss |
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Also Published As
| Publication number | Publication date |
|---|---|
| DE69032429D1 (en) | 1998-07-23 |
| AU652136B2 (en) | 1994-08-18 |
| KR100195550B1 (en) | 1999-06-15 |
| FI922151A (en) | 1992-05-12 |
| FI922151A0 (en) | 1992-05-12 |
| US5120831A (en) | 1992-06-09 |
| ES2116986T3 (en) | 1998-08-01 |
| JP3174323B2 (en) | 2001-06-11 |
| ATE167484T1 (en) | 1998-07-15 |
| AU6878191A (en) | 1991-06-13 |
| NO921875D0 (en) | 1992-05-12 |
| WO1991007431A1 (en) | 1991-05-30 |
| CA2068324A1 (en) | 1991-05-14 |
| NO921875L (en) | 1992-07-10 |
| EP0500745B1 (en) | 1998-06-17 |
| CA2068324C (en) | 2001-01-16 |
| DE69032429T2 (en) | 1998-10-15 |
| KR920703629A (en) | 1992-12-18 |
| EP0500745A1 (en) | 1992-09-02 |
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